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How do APCs find their specific T-cells in the lymph nodes?

How do APCs find their specific T-cells in the lymph nodes?



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My understanding is that when an APC (more specifically a dendritic cell) encounters an antigen in the periphery, it ingests it and presents it on its surface. It then migrates to lymph nodes to activate the T-cell that has the specific receptor for this antigen.

Now, I know that T-cells circulate throughout the body, but given the amount of the cells in a lymph node, and the fact that only a few T-cells are specific for a given antigen, it seems to me highly improbable for the APC to meet the specific T-cell.

Is it really that the APCs randomly check every T-cell there? If so, do we know how long would that take? Or is there a way to quickly locate the specific T-cell?


Anatomy and Function of Lymph Nodes

Lymph nodes are specialized masses of tissue that are situated along lymphatic system pathways. These structures filter lymph fluid before returning it to the blood. Lymph nodes, lymph vessels, and other lymphatic organs help to prevent fluid build-up in tissues, defend against infection, and maintain normal blood volume and pressure in the body. With the exception of the central nervous system (CNS), lymph nodes may be found in every area of the body.


T-cell activation

T cells are generated in the Thymus and are programmed to be specific for one particular foreign particle (antigen). Once they leave the thymus, they circulate throughout the body until they recognise their antigen on the surface of antigen presenting cells (APCs). The T cell receptor (TCR) on both CD4 + helper T cells and CD8 + cytotoxic T cells binds to the antigen as it is held in a structure called the MHC complex, on the surface of the APC. This triggers initial activation of the T cells. The CD4 and CD8 molecules then bind to the MHC molecule too, stabilising the whole structure. This initial binding between a T cell specific for one antigen and the antigen-MHC it matches sets the whole response in motion. This normally takes place in the secondary lymphoid organs.

(Credited: Shutterstock - Juan Gaertner)
Figure 1. Interaction between T cell and dendritic cell

In addition to TCR binding to antigen-loaded MHC, both helper T cells and cytotoxic T cells require a number of secondary signals to become activated and respond to the threat. In the case of helper T cells, the first of these is provided by CD28. This molecule on the T cell binds to one of two molecules on the APC – B7.1 (CD80) or B7.2 (CD86) – and initiates T-cell proliferation.

This process leads to the production of many millions of T cells that recognise the antigen. In order to control the response, stimulation of CD28 by B7 induces the production of CTLA-4 (CD152). This molecule competes with CD28 for B7 and so reduces activation signals to the T cell and winds down the immune response. Cytotoxic T cells are less reliant on CD28 for activation but do require signals from other co-stimulatory molecules such as CD70 and 4-1BB (CD137).

T cells must recognise foreign antigen strongly and specifically to mount an effective immune response and those that do are given survival signals by several molecules, including ICOS, 4-1BB and OX40. These molecules are found on the T-cell surface and are stimulated by their respective ligands which are typically found on APCs. Unlike CD28 and the TCR, ICOS, OX40 and 4-1BB are not constitutively expressed on T cells. Likewise, their respective ligands are only expressed on APCs following pathogen recognition. This is important because it ensures T cells are only activated by APCs which have encountered a pathogen and responded. Interaction of the TCR with peptide-MHC in the absence of co-stimulation switches the T cells off, so they do not respond inappropriately.

Figure 2. Schematic of early T cell activation. The T cell encounters a dendritic cell (DC) bearing its cognate peptide in an MHC molecule, and binds the peptide-MHC though CD3 and CD4 or 8. Subsequently, co-stimulation occurs through DC-bound CD86, CD80, OX40L and 4-1BBL. This induces full activation and effector function in the T cell.

Signal Three

Once the T cell has received a specific antigen signal and a general signal two, it receives more instructions in the form of cytokines. These determine which type of responder the cell will become – in the case of helper T cells, it will push them into Th1 type (cells exposed to the cytokine IL-12), Th2 (IL-4), or IL-17 (IL-6, IL-23). Each one of these cells performs a specific task in the tissue and in developing further immune responses.

The resulting cell population moves out to the site of the infection or inflammation in order to deal with the pathogen. Other cells present at the tissue site of inflammation– such as neutrophils, mast cells, and epithelial cells – can also release cytokines, chemokines, short peptides and other molecules which induce further activation and proliferation of the T cells.


Free Response

Why can&rsquot dogs catch the measles?

The virus cannot attach to dog cells because dog cells do not express the receptors for the virus or there is no cell within the dog that is permissive for viral replication.

Why is immunization after being bitten by a rabid animal so effective?

Rabies vaccine works after a bite because it takes two weeks for the virus to travel from the site of the bite to the central nervous system, where the most severe symptoms of the disease occur. The vaccine is able to cause an immune response in the body during this time that clears the infection before it reaches the nervous system.

17.2: Innate Immunity

Innate immunity is not caused by an infection or vaccination and depends initially on physical and chemical barriers that work on all pathogens, sometimes called the first line of defense. The second line of defense of the innate system includes chemical signals that produce inflammation and fever responses as well as mobilizing protective cells and other chemical defenses.


Ways in Which T-Cells Are Affected by Cancer

  • Direct involvement in cancer: In cancers such as T-cell lymphoma, the T-cells themselves are cancerous.  
  • Bone marrow takeover: Lymphomas and other cancers which spread to the bone marrow crowd out healthy stem cells in the bone marrow (precursors of T-cells) resulting in the depletion of T-cells.
  • Destruction due to chemotherapy: Chemotherapy can directly deplete T-cells and other white blood cells.

Antigen Capture and Presentation to Lymphocytes: What Lymphocytes See

Adaptive immune responses are initiated by the recognition of antigens by antigen receptors of lymphocytes. B and T lymphocytes differ in the types of antigens they recognize. The antigen receptors of B lymphocytes—namely, membrane-bound antibodies—can recognize a variety of macromolecules (proteins, polysaccharides, lipids, nucleic acids), in soluble form or cell surface–associated form, as well as small chemicals. Therefore, B cell–mediated humoral immune responses may be generated against many types of microbial cell wall and soluble antigens. The antigen receptors of most T lymphocytes, on the other hand, can see only peptide fragments of protein antigens, and only when these peptides are displayed on host cell surfaces bound to specialized proteins called major histocompatibility complex (MHC) molecules. Because the association of antigenic peptides and MHC molecules occurs inside cells, T cell–mediated immune responses may be generated only against protein antigens that are either produced in or taken up by host cells. This chapter focuses on the nature of the antigens that are recognized by lymphocytes. Chapter 4 describes the receptors used by lymphocytes to detect these antigens.

The induction of immune responses by antigens is a highly orchestrated process with a number of remarkable features. The first is that very few naive lymphocytes are specific for any one antigen, as few as 1 in 10 5 or 10 6 circulating lymphocytes, and this small fraction of the body’s lymphocytes needs to locate and react rapidly to the antigen, wherever it is introduced. Second, different types of adaptive immune responses are required to defend against different types of microbes. In fact, the immune system has to react in different ways even to the same microbe at different stages of the microbe’s life cycle. For example, defense against a microbe (e.g., a virus) that has entered the bloodstream depends on antibodies that bind the microbe, prevent it from infecting host cells, and help to eliminate it. The production of potent antibodies requires the activation of CD4 + helper T cells. After it has infected host cells, however, the microbe is safe from antibodies, which cannot enter the cells. As a result, activation of CD8 + cytotoxic T lymphocytes (CTLs) may be necessary to kill the infected cells and eliminate the reservoir of infection. Thus, we are faced with two important questions:

How do the rare naive lymphocytes specific for any microbial antigen find that microbe, especially considering that microbes may enter anywhere in the body?

How do different types of T cells recognize microbes in different cellular compartments? Specifically, helper T cells recognize and respond to both extracellular and intracellular microbes that can be internalized into vesicular compartments in host cells, whereas CTLs kill infected cells that harbor microbial antigens in the cytosol and nucleus outside vesicular compartments. As we shall see in this chapter, MHC molecules play a central role in this segregation of antigen recognition by T cells.

The answer to both questions is that the immune system has developed a highly specialized system for capturing and displaying antigens to lymphocytes. Research by immunologists, cell biologists, and biochemists has led to a sophisticated understanding of how protein antigens are captured, broken down, and displayed for recognition by T lymphocytes. This is the major topic of discussion in this chapter.

Antigens Recognized by T Lymphocytes

The majority of T lymphocytes recognize peptide antigens that are bound to and displayed by the MHC molecules of antigen-presenting cells (APCs). The MHC is a genetic locus whose principal protein products function as the peptide display molecules of the immune system. CD4 + and CD8 + T cells can see peptides only when these peptides are displayed by that individual’s MHC molecules. This property of T cells is called MHC restriction . The T cell receptor (TCR) recognizes some amino acid residues of the peptide antigen and simultaneously also recognizes residues of the MHC molecule that is displaying that peptide ( Fig. 3.1 ). Each TCR, and hence each clone of CD4 + or CD8 + T cells, recognizes one peptide displayed by one of the many MHC molecules in every individual. The properties of MHC molecules and the significance of MHC restriction are described later in this chapter. How we generate T cells that recognize peptides presented only by self MHC molecules is described in Chapter 4 . Also, some small populations of T cells recognize lipid and other nonpeptide antigens either presented by nonpolymorphic class I MHC–like molecules or without a requirement for a specialized antigen display system.

The cells that capture microbial antigens and display them for recognition by T lymphocytes are called antigen-presenting cells (APCs). Naive T lymphocytes must see protein antigens presented by dendritic cells to initiate clonal expansion and differentiation of the T cells into effector and memory cells. Differentiated effector T cells again need to see antigens, which may be presented by various kinds of APCs besides dendritic cells, to activate the effector functions of the T cells in both humoral and cell-mediated immune responses. We first describe how APCs capture and present antigens to trigger immune responses and then examine the role of MHC molecules in antigen presentation to T cells.

Capture of Protein Antigens by Antigen-Presenting Cells

Protein antigens of microbes that enter the body are captured mainly by dendritic cells and concentrated in the peripheral (secondary) lymphoid organs, where immune responses are initiated ( Fig. 3.2 ). Microbes usually enter the body through the skin (by contact), the gastrointestinal tract (by ingestion), the respiratory tract (by inhalation), and the genitourinary tract (by sexual contact). Some microbes may enter the bloodstream. Microbial antigens can also be produced in any infected tissue. Because of the vast surface area of the epithelial barriers and the large volume of blood, connective tissues, and internal organs, it would be impossible for lymphocytes of all possible specificities to efficiently patrol all these sites searching for foreign invaders instead, antigens are taken to the lymphoid organs through which lymphocytes recirculate.

Antigens are taken to peripheral lymphoid organs in two ways.

Microbes or their antigens may enter the lymph or blood and circulate to lymph nodes or spleen, respectively, where they are captured by resident dendritic cells and presented to T cells. Other APCs may also capture antigens and display them to B cells in these organs.

Dendritic cells in epithelia, connective tissues, and organs transport microbial antigens to lymphoid organs. This process involves a series of events following the encounter of dendritic cells with microbes—capture of antigens, activation of the dendritic cells, migration of the antigen-carrying cells to lymph nodes, and display of the antigen to T cells. These steps are described next.

All the interfaces between the body and the external environment are lined by continuous epithelia, which provide barriers to infection. The epithelia and subepithelial tissues contain a network of cells with long processes, called dendritic cells these cells are also present in the T cell–rich areas of peripheral lymphoid organs and, in smaller numbers, in most other organs ( Fig. 3.3 ). There are two major populations of dendritic cells, called conventional (or classical) and plasmacytoid, which differ in their locations and responses ( Fig. 3.4 ). The majority of dendritic cells in tissues and lymphoid organs belong to the classical subset. In the skin, the epidermal dendritic cells are called Langerhans cells. Plasmacytoid dendritic cells are named because of their morphologic resemblance to plasma cells they are present in the blood and tissues. Plasmacytoid dendritic cells are also the major source of type I interferons in innate immune responses to viral infections (see Chapter 2 ).


Epitope Predictions

T Cell Epitopes

Antigen presenting cells process proteins into peptides that if recognized by T cells are called T cell epitopes. Two distinct pathways facilitate the processing of exogenous and endogenous (self and foreign) proteins into peptides which were comprehensively reviewed by Blum et al. (2013) . Most peptides generated by proteolysis through 26S proteasome are transported by TAP (transporter associated with antigen processing) into the endoplasmatic reticulum where they bind to MHC class I molecules. If the affinity of the peptides to MHC class I molecules is sufficiently high, stable peptide-MHC-I complexes are transported through the Golgi apparatus to the cell surface where they are recognized by T-cell receptors (TCR) of CD8 + T cells ( Fig. 1 ). In contrast, MHC class II molecules usually bind in the endosome to peptides derived from lysosomal proteolysis of exogeneous proteins trafficked by phago- and endocyotsis. Peptide-MHC II complexes are then transported in endosomal vesicles to the cell surface where they are recognized by TCR expressed on CD4 + T cells ( Fig. 2 ). Although the binding of the peptides to MHC is crucial in defining whether peptides may become epitopes, cross-presentation of peptides generated from phagocytosed exogenous proteins by MHC class I or endogenous proteins processed in the lysosome by MHC class II complicates matters in epitope prediction-assisted vaccine design. Cross-priming of naïve CD8 + T cells mediated by cross-presentation is just one example where the choice of epitopes in a vaccine will affect primary and secondary T-cell responses ( Grotzke et al., 2017 ). Since epitope-based vaccines are meant to mimic the natural protective immunity that activates the functions of both T and B cells ( Fig. 3 ) we need to consider also B cell epitopes.

Fig. 1 . Processing, presentation and recognition of MHC class I-restricted T cell epitopes.

Modified from Fig 17.21 (a) in Karp, G., 2008. Cell and Molecular Biology. Concepts and Experiments, fifth ed. Asia: John Wiley &amp Sons (Asia) Pte. Ltd.

Fig. 2 . Processing, presentation and recognition of MHC class II restricted T cell epitopes.

Modified from Fig 17.21 (a) in Karp, G., 2008. Cell and Molecular Biology. Concepts and Experiments, fifth ed. Asia: John Wiley &amp Sons (Asia) Pte. Ltd.

Fig. 3 . Interaction of activated T helper cells activates B cells which differentiate into memory and plasma cells. The latter secrete antigen-specific antibodies.

Modified from Fig 17.10 (a) in Karp, G., 2008. Cell and Molecular Biology. Concepts and Experiments, fifth ed. Asia: John Wiley &amp Sons (Asia) Pte. Ltd.


Immune System and Inflammation Summary

Immune System Introduction

  • The immune system is able to distinguish between 'self' and 'non-self' and between normal and abnormal cells.
  • The immune system acts through two broad and somewhat overlapping mechanisms - Specific Immune Responses and Non-Specific (Innate) Immunity.

The Innate Immune System

  • The innate immune system carries out the non-specific functions.
  • The innate immune system consists of three components:
    • Physical and chemical barriers such as skin, mucus, and earwax
    • Cells including macrophages and neutrophils
    • Proteins that include enzymes found in saliva and tears

    The Acquired Immune Response

    • The acquired immune response carries out specific or adaptive immunity.
    • The adaptive response develops and changes over the course of our lifetimes.
    • The adaptive immune response is highly specific for invading pathogens.
    • T cells and B cells are the main cell types of the acquired immune system.
    • The specific immune response is characterized by the following: 1) antigen specificity, 2) diversity, 3) memory, and 4) self:non-self discrimination.
    • The adaptive immune response can detect cancer cells.

    Cells of the Acquired Immune Response

    • B cells and T cells are known as lymphocytes and they originate in the bone marrow.
    • Lymphocytes reside in lymphatic tissue such as lymph nodes and the spleen.
    • A protein or other product that can be recognized by the immune system and lead to the production of an immune response is known as an antigen.
    • B cells produce antibodies that bind tightly to a pathogen which is then inactivated or destroyed.
    • T cells mature into either helper T cells or cytotoxic T lymphocytes.

    The Immune System and Cancer

    • The immune system can recognize mutant or otherwise abnormal cells as foreign.
    • Cancer cells can mutate enough so that they are able to escape the surveillance mechanisms of the immune system.
    • Many cancers produce chemical signals that inhibit the actions of immune cells.
    • Some tumors grow in locations such as the eyes or brain, which are not regularly patrolled by immune cells.
    • Immunotherapy and cancer vaccines are designed to provide the immune system with the signals that it needs to recognize and destroy cancer cells.

    Inflammation Summary

    Inflammation is the body’s response to potentially harmful events. It is a protective and necessary process that involves recruiting cells and molecules of the host’s immune system to the site of injury. Inflammation itself can become harmful when the process is prolonged.

    Acute (short-term) inflammation is an observable physical response with four key signs:

    1. Redness
    2. Heat
    3. Swelling
    4. Pain.

    Acute inflammation has not been shown to increase cancer risk.

    Chronic (long-term) inflammation does not show the symptoms of acute inflammation. It is a prolonged immune response that often leads to tissue damage. These responses can last for many years. Chronic inflammation is different from acute inflammation, though acute inflammation can develop into chronic inflammation if the injury/infection is long-lasting or if something prevents the normal healing process. Things that can lead to chronic inflammation include persistent infections, hypersensitivity diseases, and long-term exposure to toxic agents. Research also indicates that being overweight/obese can also trigger some aspects of chronic inflammation. 42

    A summary of the features of acute and chronic inflammation

    • Fast onset (minutes or hours)
    • Recruited immune cells are mostly neutrophils
    • Causes mild and self-limiting damage to host tissue
    • Noticeable local and systemic physical symptoms (the four cardinal signs listed above. 9
    • Slower onset (days)
    • Involves recruitment of macrophages (derived from monocytes) and lymphocytes
    • Causes moderate to severe damage to host tissue
    • Chronic inflammatory conditions have been linked to increased risk of cancer. There are several ways that chronic inflammation can cause cancer, including:

    1. Causing sustained cell proliferation.
    2. Increasing the presence of growth factors.
    3. Causing changes in the proteins that surround cells (produces ‘activated’ stroma).
    4. Leading to the invasion and activation of inflammatory immune cells.
    5. Increasing the amounts of DNA damaging agents in the area.14

    There are a number of ways to potentially prevent chronic inflammation and one of the most significant is avoiding being overweight or obese.

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    42.2 Adaptive Immune Response

    By the end of this section, you will be able to do the following:

    • Explain adaptive immunity
    • Compare and contrast adaptive and innate immunity
    • Describe cell-mediated immune response and humoral immune response
    • Describe immune tolerance

    The adaptive, or acquired, immune response takes days or even weeks to become established—much longer than the innate response however, adaptive immunity is more specific to pathogens and has memory. Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. This part of the immune system is activated when the innate immune response is insufficient to control an infection. In fact, without information from the innate immune system, the adaptive response could not be mobilized. There are two types of adaptive responses: the cell-mediated immune response , which is carried out by T cells, and the humoral immune response , which is controlled by activated B cells and antibodies. Activated T cells and B cells that are specific to molecular structures on the pathogen proliferate and attack the invading pathogen. Their attack can kill pathogens directly or secrete antibodies that enhance the phagocytosis of pathogens and disrupt the infection. Adaptive immunity also involves a memory to provide the host with long-term protection from reinfection with the same type of pathogen on reexposure, this memory will facilitate an efficient and quick response.

    Antigen-presenting Cells

    Unlike NK cells of the innate immune system, B cells (B lymphocytes) are a type of white blood cell that gives rise to antibodies, whereas T cells (T lymphocytes) are a type of white blood cell that plays an important role in the immune response. T cells are a key component in the cell-mediated response—the specific immune response that utilizes T cells to neutralize cells that have been infected with viruses and certain bacteria. There are three types of T cells: cytotoxic, helper, and suppressor T cells. Cytotoxic T cells destroy virus-infected cells in the cell-mediated immune response, and helper T cells play a part in activating both the antibody and the cell-mediated immune responses. Suppressor T cells deactivate T cells and B cells when needed, and thus prevent the immune response from becoming too intense.

    An antigen is a foreign or “non-self” macromolecule that reacts with cells of the immune system. Not all antigens will provoke a response. For instance, individuals produce innumerable “self” antigens and are constantly exposed to harmless foreign antigens, such as food proteins, pollen, or dust components. The suppression of immune responses to harmless macromolecules is highly regulated and typically prevents processes that could be damaging to the host, known as tolerance.

    The innate immune system contains cells that detect potentially harmful antigens, and then inform the adaptive immune response about the presence of these antigens. An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytose the pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. Dendritic cells are immune cells that process antigen material they are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, thus functioning as an antigen-presenting cell. Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs.

    After phagocytosis by APCs, the phagocytic vesicle fuses with an intracellular lysosome forming phagolysosome. Within the phagolysosome, the components are broken down into fragments the fragments are then loaded onto MHC class I or MHC class II molecules and are transported to the cell surface for antigen presentation, as illustrated in Figure 42.8. Note that T lymphocytes cannot properly respond to the antigen unless it is processed and embedded in an MHC II molecule. APCs express MHC on their surfaces, and when combined with a foreign antigen, these complexes signal a “non-self” invader. Once the fragment of antigen is embedded in the MHC II molecule, the immune cell can respond. Helper T cells are one of the main lymphocytes that respond to antigen-presenting cells. Recall that all other nucleated cells of the body expressed MHC I molecules, which signal “healthy” or “normal.”

    Link to Learning

    This animation from Rockefeller University shows how dendritic cells act as sentinels in the body's immune system.

    T and B Lymphocytes

    Lymphocytes in human circulating blood are approximately 80 to 90 percent T cells, shown in Figure 42.9, and 10 to 20 percent B cells. Recall that the T cells are involved in the cell-mediated immune response, whereas B cells are part of the humoral immune response.

    T cells encompass a heterogeneous population of cells with extremely diverse functions. Some T cells respond to APCs of the innate immune system, and indirectly induce immune responses by releasing cytokines. Other T cells stimulate B cells to prepare their own response. Another population of T cells detects APC signals and directly kills the infected cells. Other T cells are involved in suppressing inappropriate immune reactions to harmless or “self” antigens.

    T and B cells exhibit a common theme of recognition/binding of specific antigens via a complementary receptor, followed by activation and self-amplification/maturation to specifically bind to the particular antigen of the infecting pathogen. T and B lymphocytes are also similar in that each cell only expresses one type of antigen receptor. Any individual may possess a population of T and B cells that together express a near limitless variety of antigen receptors that are capable of recognizing virtually any infecting pathogen. T and B cells are activated when they recognize small components of antigens, called epitopes , presented by APCs, illustrated in Figure 42.10. Note that recognition occurs at a specific epitope rather than on the entire antigen for this reason, epitopes are known as “antigenic determinants.” In the absence of information from APCs, T and B cells remain inactive, or naïve, and are unable to prepare an immune response. The requirement for information from the APCs of innate immunity to trigger B cell or T cell activation illustrates the essential nature of the innate immune response to the functioning of the entire immune system.

    Naïve T cells can express one of two different molecules, CD4 or CD8, on their surface, as shown in Figure 42.11, and are accordingly classified as CD4 + or CD8 + cells. These molecules are important because they regulate how a T cell will interact with and respond to an APC. Naïve CD4 + cells bind APCs via their antigen-embedded MHC II molecules and are stimulated to become helper T (TH) lymphocytes , cells that go on to stimulate B cells (or cytotoxic T cells) directly or secrete cytokines to inform more and various target cells about the pathogenic threat. In contrast, CD8 + cells engage antigen-embedded MHC I molecules on APCs and are stimulated to become cytotoxic T lymphocytes (CTLs) , which directly kill infected cells by apoptosis and emit cytokines to amplify the immune response. The two populations of T cells have different mechanisms of immune protection, but both bind MHC molecules via their antigen receptors called T cell receptors (TCRs). The CD4 or CD8 surface molecules differentiate whether the TCR will engage an MHC II or an MHC I molecule. Because they assist in binding specificity, the CD4 and CD8 molecules are described as coreceptors.

    Visual Connection

    Which of the following statements about T cells is false?

    1. Helper T cells release cytokines while cytotoxic T cells kill the infected cell.
    2. Helper T cells are CD4 + , while cytotoxic T cells are CD8 + .
    3. MHC II is a receptor found on most body cells, while MHC I is a receptor found on immune cells only.
    4. The T cell receptor is found on both CD4 + and CD8 + T cells.

    Consider the innumerable possible antigens that an individual will be exposed to during a lifetime. The mammalian adaptive immune system is adept in responding appropriately to each antigen. Mammals have an enormous diversity of T cell populations, resulting from the diversity of TCRs. Each TCR consists of two polypeptide chains that span the T cell membrane, as illustrated in Figure 42.12 the chains are linked by a disulfide bridge. Each polypeptide chain is comprised of a constant domain and a variable domain: a domain, in this sense, is a specific region of a protein that may be regulatory or structural. The intracellular domain is involved in intracellular signaling. A single T cell will express thousands of identical copies of one specific TCR variant on its cell surface. The specificity of the adaptive immune system occurs because it synthesizes millions of different T cell populations, each expressing a TCR that differs in its variable domain. This TCR diversity is achieved by the mutation and recombination of genes that encode these receptors in stem cell precursors of T cells. The binding between an antigen-displaying MHC molecule and a complementary TCR “match” indicates that the adaptive immune system needs to activate and produce that specific T cell because its structure is appropriate to recognize and destroy the invading pathogen.

    Helper T Lymphocytes

    The TH lymphocytes function indirectly to identify potential pathogens for other cells of the immune system. These cells are important for extracellular infections, such as those caused by certain bacteria, helminths, and protozoa. TH lymphocytes recognize specific antigens displayed in the MHC II complexes of APCs. There are two major populations of TH cells: TH1 and TH2. TH1 cells secrete cytokines to enhance the activities of macrophages and other T cells. TH1 cells activate the action of cyotoxic T cells, as well as macrophages. TH2 cells stimulate naïve B cells to destroy foreign invaders via antibody secretion. Whether a TH1 or a TH2 immune response develops depends on the specific types of cytokines secreted by cells of the innate immune system, which in turn depends on the nature of the invading pathogen.

    The TH1-mediated response involves macrophages and is associated with inflammation. Recall the frontline defenses of macrophages involved in the innate immune response. Some intracellular bacteria, such as Mycobacterium tuberculosis, have evolved to multiply in macrophages after they have been engulfed. These pathogens evade attempts by macrophages to destroy and digest the pathogen. When M. tuberculosis infection occurs, macrophages can stimulate naïve T cells to become TH1 cells. These stimulated T cells secrete specific cytokines that send feedback to the macrophage to stimulate its digestive capabilities and allow it to destroy the colonizing M. tuberculosis. In the same manner, TH1-activated macrophages also become better suited to ingest and kill tumor cells. In summary TH1 responses are directed toward intracellular invaders while TH2 responses are aimed at those that are extracellular.

    B Lymphocytes

    When stimulated by the TH2 pathway, naïve B cells differentiate into antibody-secreting plasma cells. A plasma cell is an immune cell that secrets antibodies these cells arise from B cells that were stimulated by antigens. Similar to T cells, naïve B cells initially are coated in thousands of B cell receptors (BCRs), which are membrane-bound forms of Ig (immunoglobulin, or an antibody). The B cell receptor has two heavy chains and two light chains connected by disulfide linkages. Each chain has a constant and a variable region the latter is involved in antigen binding. Two other membrane proteins, Ig alpha and Ig beta, are involved in signaling. The receptors of any particular B cell, as shown in Figure 42.13 are all the same, but the hundreds of millions of different B cells in an individual have distinct recognition domains that contribute to extensive diversity in the types of molecular structures to which they can bind. In this state, B cells function as APCs. They bind and engulf foreign antigens via their BCRs and then display processed antigens in the context of MHC II molecules to TH2 cells. When a TH2 cell detects that a B cell is bound to a relevant antigen, it secretes specific cytokines that induce the B cell to proliferate rapidly, which makes thousands of identical (clonal) copies of it, and then it synthesizes and secretes antibodies with the same antigen recognition pattern as the BCRs. The activation of B cells corresponding to one specific BCR variant and the dramatic proliferation of that variant is known as clonal selection . This phenomenon drastically, but briefly, changes the proportions of BCR variants expressed by the immune system, and shifts the balance toward BCRs specific to the infecting pathogen.

    T and B cells differ in one fundamental way: whereas T cells bind antigens that have been digested and embedded in MHC molecules by APCs, B cells function as APCs that bind intact antigens that have not been processed. Although T and B cells both react with molecules that are termed “antigens,” these lymphocytes actually respond to very different types of molecules. B cells must be able to bind intact antigens because they secrete antibodies that must recognize the pathogen directly, rather than digested remnants of the pathogen. Bacterial carbohydrate and lipid molecules can activate B cells independently from the T cells.

    Cytotoxic T Lymphocytes

    CTLs, a subclass of T cells, function to clear infections directly. The cell-mediated part of the adaptive immune system consists of CTLs that attack and destroy infected cells. CTLs are particularly important in protecting against viral infections this is because viruses replicate within cells where they are shielded from extracellular contact with circulating antibodies. When APCs phagocytize pathogens and present MHC I-embedded antigens to naïve CD8 + T cells that express complementary TCRs, the CD8 + T cells become activated to proliferate according to clonal selection. These resulting CTLs then identify non-APCs displaying the same MHC I-embedded antigens (for example, viral proteins)—for example, the CTLs identify infected host cells.

    Intracellularly, infected cells typically die after the infecting pathogen replicates to a sufficient concentration and lyses the cell, as many viruses do. CTLs attempt to identify and destroy infected cells before the pathogen can replicate and escape, thereby halting the progression of intracellular infections. CTLs also support NK lymphocytes to destroy early cancers. Cytokines secreted by the TH1 response that stimulates macrophages also stimulate CTLs and enhance their ability to identify and destroy infected cells and tumors.

    CTLs sense MHC I-embedded antigens by directly interacting with infected cells via their TCRs. Binding of TCRs with antigens activates CTLs to release perforin and granzyme, degradative enzymes that will induce apoptosis of the infected cell. Recall that this is a similar destruction mechanism to that used by NK cells. In this process, the CTL does not become infected and is not harmed by the secretion of perforin and granzymes. In fact, the functions of NK cells and CTLs are complementary and maximize the removal of infected cells, as illustrated in Figure 42.14. If the NK cell cannot identify the “missing self” pattern of down-regulated MHC I molecules, then the CTL can identify it by the complex of MHC I with foreign antigens, which signals “altered self.” Similarly, if the CTL cannot detect antigen-embedded MHC I because the receptors are depleted from the cell surface, NK cells will destroy the cell instead. CTLs also emit cytokines, such as interferons, that alter surface protein expression in other infected cells, such that the infected cells can be easily identified and destroyed. Moreover, these interferons can also prevent virally infected cells from releasing virus particles.

    Visual Connection

    Based on what you know about MHC receptors, why do you think an organ transplanted from an incompatible donor to a recipient will be rejected?

    Plasma cells and CTLs are collectively called effector cells : they represent differentiated versions of their naïve counterparts, and they are involved in bringing about the immune defense of killing pathogens and infected host cells.

    Mucosal Surfaces and Immune Tolerance

    The innate and adaptive immune responses discussed thus far comprise the systemic immune system (affecting the whole body), which is distinct from the mucosal immune system. Mucosal immunity is formed by mucosa-associated lymphoid tissue, which functions independently of the systemic immune system, and which has its own innate and adaptive components. Mucosa-associated lymphoid tissue (MALT) , illustrated in Figure 42.15, is a collection of lymphatic tissue that combines with epithelial tissue lining the mucosa throughout the body. This tissue functions as the immune barrier and response in areas of the body with direct contact to the external environment. The systemic and mucosal immune systems use many of the same cell types. Foreign particles that make their way to MALT are taken up by absorptive epithelial cells called M cells and delivered to APCs located directly below the mucosal tissue. M cells function in the transport described, and are located in the Peyer’s patch, a lymphoid nodule. APCs of the mucosal immune system are primarily dendritic cells, with B cells and macrophages having minor roles. Processed antigens displayed on APCs are detected by T cells in the MALT and at various mucosal induction sites, such as the tonsils, adenoids, appendix, or the mesenteric lymph nodes of the intestine. Activated T cells then migrate through the lymphatic system and into the circulatory system to mucosal sites of infection.

    MALT is a crucial component of a functional immune system because mucosal surfaces, such as the nasal passages, are the first tissues onto which inhaled or ingested pathogens are deposited. The mucosal tissue includes the mouth, pharynx, and esophagus, and the gastrointestinal, respiratory, and urogenital tracts.

    The immune system has to be regulated to prevent wasteful, unnecessary responses to harmless substances, and more importantly so that it does not attack “self.” The acquired ability to prevent an unnecessary or harmful immune response to a detected foreign substance known not to cause disease is described as immune tolerance . Immune tolerance is crucial for maintaining mucosal homeostasis given the tremendous number of foreign substances (such as food proteins) that APCs of the oral cavity, pharynx, and gastrointestinal mucosa encounter. Immune tolerance is brought about by specialized APCs in the liver, lymph nodes, small intestine, and lung that present harmless antigens to an exceptionally diverse population of regulatory T (Treg) cells , specialized lymphocytes that suppress local inflammation and inhibit the secretion of stimulatory immune factors. The combined result of Treg cells is to prevent immunologic activation and inflammation in undesired tissue compartments and to allow the immune system to focus on pathogens instead. In addition to promoting immune tolerance of harmless antigens, other subsets of Treg cells are involved in the prevention of the autoimmune response , which is an inappropriate immune response to host cells or self-antigens. Another Treg class suppresses immune responses to harmful pathogens after the infection has cleared to minimize host cell damage induced by inflammation and cell lysis.

    Immunological Memory

    The adaptive immune system possesses a memory component that allows for an efficient and dramatic response upon reinvasion of the same pathogen. Memory is handled by the adaptive immune system with little reliance on cues from the innate response. During the adaptive immune response to a pathogen that has not been encountered before, called a primary response, plasma cells secreting antibodies and differentiated T cells increase, then plateau over time. As B and T cells mature into effector cells, a subset of the naïve populations differentiates into B and T memory cells with the same antigen specificities, as illustrated in Figure 42.16.

    A memory cell is an antigen-specific B or T lymphocyte that does not differentiate into effector cells during the primary immune response, but that can immediately become effector cells upon reexposure to the same pathogen. During the primary immune response, memory cells do not respond to antigens and do not contribute to host defenses. As the infection is cleared and pathogenic stimuli subside, the effectors are no longer needed, and they undergo apoptosis. In contrast, the memory cells persist in the circulation.

    Visual Connection

    The Rh antigen is found on Rh-positive red blood cells. An Rh-negative female can usually carry an Rh-positive fetus to term without difficulty. However, if she has a second Rh-positive fetus, her body may launch an immune attack that causes hemolytic disease of the newborn. Why do you think hemolytic disease is only a problem during the second or subsequent pregnancies?

    If the pathogen is never encountered again during the individual’s lifetime, B and T memory cells will circulate for a few years or even several decades and will gradually die off, having never functioned as effector cells. However, if the host is reexposed to the same pathogen type, circulating memory cells will immediately differentiate into plasma cells and CTLs without input from APCs or TH cells. One reason the adaptive immune response is delayed is because it takes time for naïve B and T cells with the appropriate antigen specificities to be identified and activated. Upon reinfection, this step is skipped, and the result is a more rapid production of immune defenses. Memory B cells that differentiate into plasma cells output tens to hundreds-fold greater antibody amounts than were secreted during the primary response, as the graph in Figure 42.17 illustrates. This rapid and dramatic antibody response may stop the infection before it can even become established, and the individual may not realize he or she had been exposed.

    Vaccination is based on the knowledge that exposure to noninfectious antigens, derived from known pathogens, generates a mild primary immune response. The immune response to vaccination may not be perceived by the host as illness but still confers immune memory. When exposed to the corresponding pathogen to which an individual was vaccinated, the reaction is similar to a secondary exposure. Because each reinfection generates more memory cells and increased resistance to the pathogen, and because some memory cells die, certain vaccine courses involve one or more booster vaccinations to mimic repeat exposures: for instance, tetanus boosters are necessary every ten years because the memory cells only live that long.

    Mucosal Immune Memory

    A subset of T and B cells of the mucosal immune system differentiates into memory cells just as in the systemic immune system. Upon reinvasion of the same pathogen type, a pronounced immune response occurs at the mucosal site where the original pathogen deposited, but a collective defense is also organized within interconnected or adjacent mucosal tissue. For instance, the immune memory of an infection in the oral cavity would also elicit a response in the pharynx if the oral cavity was exposed to the same pathogen.

    Career Connection

    Vaccinologist

    Vaccination (or immunization) involves the delivery, usually by injection as shown in Figure 42.18, of noninfectious antigen(s) derived from known pathogens. Other components, called adjuvants, are delivered in parallel to help stimulate the immune response. Immunological memory is the reason vaccines work. Ideally, the effect of vaccination is to elicit immunological memory, and thus resistance to specific pathogens without the individual having to experience an infection.

    Vaccinologists are involved in the process of vaccine development from the initial idea to the availability of the completed vaccine. This process can take decades, can cost millions of dollars, and can involve many obstacles along the way. For instance, injected vaccines stimulate the systemic immune system, eliciting humoral and cell-mediated immunity, but have little effect on the mucosal response, which presents a challenge because many pathogens are deposited and replicate in mucosal compartments, and the injection does not provide the most efficient immune memory for these disease agents. For this reason, vaccinologists are actively involved in developing new vaccines that are applied via intranasal, aerosol, oral, or transcutaneous (absorbed through the skin) delivery methods. Importantly, mucosal-administered vaccines elicit both mucosal and systemic immunity and produce the same level of disease resistance as injected vaccines.

    Currently, a version of intranasal influenza vaccine is available, and the polio and typhoid vaccines can be administered orally, as shown in Figure 42.19. Similarly, the measles and rubella vaccines are being adapted to aerosol delivery using inhalation devices. Eventually, transgenic plants may be engineered to produce vaccine antigens that can be eaten to confer disease resistance. Other vaccines may be adapted to rectal or vaginal application to elicit immune responses in rectal, genitourinary, or reproductive mucosa. Finally, vaccine antigens may be adapted to transdermal application in which the skin is lightly scraped and microneedles are used to pierce the outermost layer. In addition to mobilizing the mucosal immune response, this new generation of vaccines may end the anxiety associated with injections and, in turn, improve patient participation.

    Primary Centers of the Immune System

    Although the immune system is characterized by circulating cells throughout the body, the regulation, maturation, and intercommunication of immune factors occur at specific sites. The blood circulates immune cells, proteins, and other factors through the body. Approximately 0.1 percent of all cells in the blood are leukocytes, which encompass monocytes (the precursor of macrophages) and lymphocytes. The majority of cells in the blood are erythrocytes (red blood cells). Lymph is a watery fluid that bathes tissues and organs with protective white blood cells and does not contain erythrocytes. Cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial space, by a process called extravasation (passing through to surrounding tissue).

    The cells of the immune system originate from hematopoietic stem cells in the bone marrow. Cytokines stimulate these stem cells to differentiate into immune cells. B cell maturation occurs in the bone marrow, whereas naïve T cells transit from the bone marrow to the thymus for maturation. In the thymus, immature T cells that express TCRs complementary to self-antigens are destroyed. This process helps prevent autoimmune responses.

    On maturation, T and B lymphocytes circulate to various destinations. Lymph nodes scattered throughout the body, as illustrated in Figure 42.20, house large populations of T and B cells, dendritic cells, and macrophages. Lymph gathers antigens as it drains from tissues. These antigens then are filtered through lymph nodes before the lymph is returned to circulation. APCs in the lymph nodes capture and process antigens and inform nearby lymphocytes about potential pathogens.

    The spleen houses B and T cells, macrophages, dendritic cells, and NK cells. The spleen, shown in Figure 42.21, is the site where APCs that have trapped foreign particles in the blood can communicate with lymphocytes. Antibodies are synthesized and secreted by activated plasma cells in the spleen, and the spleen filters foreign substances and antibody-complexed pathogens from the blood. Functionally, the spleen is to the blood as lymph nodes are to the lymph.


    Adaptive Immune Response

    The adaptive, or acquired, immune response takes days or even weeks to become established—much longer than the innate response however, adaptive immunity is more specific to pathogens and has memory. Adaptive immunity is an immunity that occurs after exposure to an antigen either from a pathogen or a vaccination. This part of the immune system is activated when the innate immune response is insufficient to control an infection. In fact, without information from the innate immune system, the adaptive response could not be mobilized. There are two types of adaptive responses: the cell-mediated immune response, which is carried out by T cells, and the humoral immune response, which is controlled by activated B cells and antibodies. Activated T cells and B cells that are specific to molecular structures on the pathogen proliferate and attack the invading pathogen. Their attack can kill pathogens directly or secrete antibodies that enhance the phagocytosis of pathogens and disrupt the infection. Adaptive immunity also involves a memory to provide the host with long-term protection from reinfection with the same type of pathogen on re-exposure, this memory will facilitate an efficient and quick response.

    Antigen-presenting Cells

    Unlike NK cells of the innate immune system, B cells (B lymphocytes) are a type of white blood cell that gives rise to antibodies, whereas T cells (T lymphocytes) are a type of white blood cell that plays an important role in the immune response. T cells are a key component in the cell-mediated response—the specific immune response that utilizes T cells to neutralize cells that have been infected with viruses and certain bacteria. There are three types of T cells: cytotoxic, helper, and suppressor T cells. Cytotoxic T cells destroy virus-infected cells in the cell-mediated immune response, and helper T cells play a part in activating both the antibody and the cell-mediated immune responses. Suppressor T cells deactivate T cells and B cells when needed, and thus prevent the immune response from becoming too intense.

    An antigen is a foreign or “non-self” macromolecule that reacts with cells of the immune system. Not all antigens will provoke a response. For instance, individuals produce innumerable “self” antigens and are constantly exposed to harmless foreign antigens, such as food proteins, pollen, or dust components. The suppression of immune responses to harmless macromolecules is highly regulated and typically prevents processes that could be damaging to the host, known as tolerance.

    The innate immune system contains cells that detect potentially harmful antigens, and then inform the adaptive immune response about the presence of these antigens. An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytose the pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. Dendritic cells are immune cells that process antigen material they are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, thus functioning as an antigen-presenting cell. Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs.

    After phagocytosis by APCs, the phagocytic vesicle fuses with an intracellular lysosome forming phagolysosome. Within the phagolysosome, the components are broken down into fragments the fragments are then loaded onto MHC class I or MHC class II molecules and are transported to the cell surface for antigen presentation, as illustrated in [link]. Note that T lymphocytes cannot properly respond to the antigen unless it is processed and embedded in an MHC II molecule. APCs express MHC on their surfaces, and when combined with a foreign antigen, these complexes signal a “non-self” invader. Once the fragment of antigen is embedded in the MHC II molecule, the immune cell can respond. Helper T- cells are one of the main lymphocytes that respond to antigen-presenting cells. Recall that all other nucleated cells of the body expressed MHC I molecules, which signal “healthy” or “normal.”

    This animation from Rockefeller University shows how dendritic cells act as sentinels in the body's immune system.

    T and B Lymphocytes

    Lymphocytes in human circulating blood are approximately 80 to 90 percent T cells, shown in [link], and 10 to 20 percent B cells. Recall that the T cells are involved in the cell-mediated immune response, whereas B cells are part of the humoral immune response.

    T cells encompass a heterogeneous population of cells with extremely diverse functions. Some T cells respond to APCs of the innate immune system, and indirectly induce immune responses by releasing cytokines. Other T cells stimulate B cells to prepare their own response. Another population of T cells detects APC signals and directly kills the infected cells. Other T cells are involved in suppressing inappropriate immune reactions to harmless or “self” antigens.

    T and B cells exhibit a common theme of recognition/binding of specific antigens via a complementary receptor, followed by activation and self-amplification/maturation to specifically bind to the particular antigen of the infecting pathogen. T and B lymphocytes are also similar in that each cell only expresses one type of antigen receptor. Any individual may possess a population of T and B cells that together express a near limitless variety of antigen receptors that are capable of recognizing virtually any infecting pathogen. T and B cells are activated when they recognize small components of antigens, called epitopes, presented by APCs, illustrated in [link]. Note that recognition occurs at a specific epitope rather than on the entire antigen for this reason, epitopes are known as “antigenic determinants.” In the absence of information from APCs, T and B cells remain inactive, or naïve, and are unable to prepare an immune response. The requirement for information from the APCs of innate immunity to trigger B cell or T cell activation illustrates the essential nature of the innate immune response to the functioning of the entire immune system.

    Naïve T cells can express one of two different molecules, CD4 or CD8, on their surface, as shown in [link], and are accordingly classified as CD4 + or CD8 + cells. These molecules are important because they regulate how a T cell will interact with and respond to an APC. Naïve CD4 + cells bind APCs via their antigen-embedded MHC II molecules and are stimulated to become helper T (TH) lymphocytes, cells that go on to stimulate B cells (or cytotoxic T cells) directly or secrete cytokines to inform more and various target cells about the pathogenic threat. In contrast, CD8 + cells engage antigen-embedded MHC I molecules on APCs and are stimulated to become cytotoxic T lymphocytes (CTLs), which directly kill infected cells by apoptosis and emit cytokines to amplify the immune response. The two populations of T cells have different mechanisms of immune protection, but both bind MHC molecules via their antigen receptors called T cell receptors (TCRs). The CD4 or CD8 surface molecules differentiate whether the TCR will engage an MHC II or an MHC I molecule. Because they assist in binding specificity, the CD4 and CD8 molecules are described as coreceptors.

    Which of the following statements about T cells is false?

    1. Helper T cells release cytokines while cytotoxic T cells kill the infected cell.
    2. Helper T cells are CD4 + , while cytotoxic T cells are CD8 + .
    3. MHC II is a receptor found on most body cells, while MHC I is a receptor found on immune cells only.
    4. The T cell receptor is found on both CD4 + and CD8 + T cells.

    Consider the innumerable possible antigens that an individual will be exposed to during a lifetime. The mammalian adaptive immune system is adept in responding appropriately to each antigen. Mammals have an enormous diversity of T cell populations, resulting from the diversity of TCRs. Each TCR consists of two polypeptide chains that span the T cell membrane, as illustrated in [link] the chains are linked by a disulfide bridge. Each polypeptide chain is comprised of a constant domain and a variable domain: a domain, in this sense, is a specific region of a protein that may be regulatory or structural. The intracellular domain is involved in intracellular signaling. A single T cell will express thousands of identical copies of one specific TCR variant on its cell surface. The specificity of the adaptive immune system occurs because it synthesizes millions of different T cell populations, each expressing a TCR that differs in its variable domain. This TCR diversity is achieved by the mutation and recombination of genes that encode these receptors in stem cell precursors of T cells. The binding between an antigen-displaying MHC molecule and a complementary TCR “match” indicates that the adaptive immune system needs to activate and produce that specific T cell because its structure is appropriate to recognize and destroy the invading pathogen.

    Helper T Lymphocytes

    The TH lymphocytes function indirectly to identify potential pathogens for other cells of the immune system. These cells are important for extracellular infections, such as those caused by certain bacteria, helminths, and protozoa. TH lymphocytes recognize specific antigens displayed in the MHC II complexes of APCs. There are two major populations of TH cells: TH1 and TH2. TH1 cells secrete cytokines to enhance the activities of macrophages and other T cells. TH1 cells activate the action of cyotoxic T cells, as well as macrophages. TH2 cells stimulate naïve B cells to destroy foreign invaders via antibody secretion. Whether a TH1 or a TH2 immune response develops depends on the specific types of cytokines secreted by cells of the innate immune system, which in turn depends on the nature of the invading pathogen.

    The TH1-mediated response involves macrophages and is associated with inflammation. Recall the frontline defenses of macrophages involved in the innate immune response. Some intracellular bacteria, such as Mycobacterium tuberculosis, have evolved to multiply in macrophages after they have been engulfed. These pathogens evade attempts by macrophages to destroy and digest the pathogen. When M. tuberculosis infection occurs, macrophages can stimulate naïve T cells to become TH1 cells. These stimulated T cells secrete specific cytokines that send feedback to the macrophage to stimulate its digestive capabilities and allow it to destroy the colonizing M. tuberculosis. In the same manner, TH1-activated macrophages also become better suited to ingest and kill tumor cells. In summary TH1 responses are directed toward intracellular invaders while TH2 responses are aimed at those that are extracellular.

    B Lymphocytes

    When stimulated by the TH2 pathway, naïve B cells differentiate into antibody-secreting plasma cells. A plasma cell is an immune cell that secrets antibodies these cells arise from B cells that were stimulated by antigens. Similar to T cells, naïve B cells initially are coated in thousands of B cell receptors (BCRs), which are membrane-bound forms of Ig (immunoglobulin, or an antibody). The B cell receptor has two heavy chains and two light chains connected by disulfide linkages. Each chain has a constant and a variable region the latter is involved in antigen binding. Two other membrane proteins, Ig alpha and Ig beta, are involved in signaling. The receptors of any particular B cell, as shown in [link] are all the same, but the hundreds of millions of different B cells in an individual have distinct recognition domains that contribute to extensive diversity in the types of molecular structures to which they can bind. In this state, B cells function as APCs. They bind and engulf foreign antigens via their BCRs and then display processed antigens in the context of MHC II molecules to TH2 cells. When a TH2 cell detects that a B cell is bound to a relevant antigen, it secretes specific cytokines that induce the B cell to proliferate rapidly, which makes thousands of identical (clonal) copies of it, and then it synthesizes and secretes antibodies with the same antigen recognition pattern as the BCRs. The activation of B cells corresponding to one specific BCR variant and the dramatic proliferation of that variant is known as clonal selection. This phenomenon drastically, but briefly, changes the proportions of BCR variants expressed by the immune system, and shifts the balance toward BCRs specific to the infecting pathogen.

    T and B cells differ in one fundamental way: whereas T cells bind antigens that have been digested and embedded in MHC molecules by APCs, B cells function as APCs that bind intact antigens that have not been processed. Although T and B cells both react with molecules that are termed “antigens,” these lymphocytes actually respond to very different types of molecules. B cells must be able to bind intact antigens because they secrete antibodies that must recognize the pathogen directly, rather than digested remnants of the pathogen. Bacterial carbohydrate and lipid molecules can activate B cells independently from the T cells.

    Cytotoxic T Lymphocytes

    CTLs, a subclass of T cells, function to clear infections directly. The cell-mediated part of the adaptive immune system consists of CTLs that attack and destroy infected cells. CTLs are particularly important in protecting against viral infections this is because viruses replicate within cells where they are shielded from extracellular contact with circulating antibodies. When APCs phagocytize pathogens and present MHC I-embedded antigens to naïve CD8 + T cells that express complementary TCRs, the CD8 + T cells become activated to proliferate according to clonal selection. These resulting CTLs then identify non-APCs displaying the same MHC I-embedded antigens (for example, viral proteins)—for example, the CTLs identify infected host cells.

    Intracellularly, infected cells typically die after the infecting pathogen replicates to a sufficient concentration and lyses the cell, as many viruses do. CTLs attempt to identify and destroy infected cells before the pathogen can replicate and escape, thereby halting the progression of intracellular infections. CTLs also support NK lymphocytes to destroy early cancers. Cytokines secreted by the TH1 response that stimulates macrophages also stimulate CTLs and enhance their ability to identify and destroy infected cells and tumors.

    CTLs sense MHC I-embedded antigens by directly interacting with infected cells via their TCRs. Binding of TCRs with antigens activates CTLs to release perforin and granzyme, degradative enzymes that will induce apoptosis of the infected cell. Recall that this is a similar destruction mechanism to that used by NK cells. In this process, the CTL does not become infected and is not harmed by the secretion of perforin and granzymes. In fact, the functions of NK cells and CTLs are complementary and maximize the removal of infected cells, as illustrated in [link]. If the NK cell cannot identify the “missing self” pattern of down-regulated MHC I molecules, then the CTL can identify it by the complex of MHC I with foreign antigens, which signals “altered self.” Similarly, if the CTL cannot detect antigen-embedded MHC I because the receptors are depleted from the cell surface, NK cells will destroy the cell instead. CTLs also emit cytokines, such as interferons, that alter surface protein expression in other infected cells, such that the infected cells can be easily identified and destroyed. Moreover, these interferons can also prevent virally infected cells from releasing virus particles.

    Based on what you know about MHC receptors, why do you think an organ transplanted from an incompatible donor to a recipient will be rejected?

    Plasma cells and CTLs are collectively called effector cells: they represent differentiated versions of their naïve counterparts, and they are involved in bringing about the immune defense of killing pathogens and infected host cells.

    Mucosal Surfaces and Immune Tolerance

    The innate and adaptive immune responses discussed thus far comprise the systemic immune system (affecting the whole body), which is distinct from the mucosal immune system. Mucosal immunity is formed by mucosa-associated lymphoid tissue, which functions independently of the systemic immune system, and which has its own innate and adaptive components. Mucosa-associated lymphoid tissue (MALT), illustrated in [link], is a collection of lymphatic tissue that combines with epithelial tissue lining the mucosa throughout the body. This tissue functions as the immune barrier and response in areas of the body with direct contact to the external environment. The systemic and mucosal immune systems use many of the same cell types. Foreign particles that make their way to MALT are taken up by absorptive epithelial cells called M cells and delivered to APCs located directly below the mucosal tissue. M cells function in the transport described, and are located in the Peyer’s patch, a lymphoid nodule. APCs of the mucosal immune system are primarily dendritic cells, with B cells and macrophages having minor roles. Processed antigens displayed on APCs are detected by T cells in the MALT and at various mucosal induction sites, such as the tonsils, adenoids, appendix, or the mesenteric lymph nodes of the intestine. Activated T cells then migrate through the lymphatic system and into the circulatory system to mucosal sites of infection.

    MALT is a crucial component of a functional immune system because mucosal surfaces, such as the nasal passages, are the first tissues onto which inhaled or ingested pathogens are deposited. The mucosal tissue includes the mouth, pharynx, and esophagus, and the gastrointestinal, respiratory, and urogenital tracts.

    The immune system has to be regulated to prevent wasteful, unnecessary responses to harmless substances, and more importantly so that it does not attack “self.” The acquired ability to prevent an unnecessary or harmful immune response to a detected foreign substance known not to cause disease is described as immune tolerance. Immune tolerance is crucial for maintaining mucosal homeostasis given the tremendous number of foreign substances (such as food proteins) that APCs of the oral cavity, pharynx, and gastrointestinal mucosa encounter. Immune tolerance is brought about by specialized APCs in the liver, lymph nodes, small intestine, and lung that present harmless antigens to an exceptionally diverse population of regulatory T (Treg) cells, specialized lymphocytes that suppress local inflammation and inhibit the secretion of stimulatory immune factors. The combined result of Treg cells is to prevent immunologic activation and inflammation in undesired tissue compartments and to allow the immune system to focus on pathogens instead. In addition to promoting immune tolerance of harmless antigens, other subsets of Treg cells are involved in the prevention of the autoimmune response, which is an inappropriate immune response to host cells or self-antigens. Another Treg class suppresses immune responses to harmful pathogens after the infection has cleared to minimize host cell damage induced by inflammation and cell lysis.

    Immunological Memory

    The adaptive immune system possesses a memory component that allows for an efficient and dramatic response upon reinvasion of the same pathogen. Memory is handled by the adaptive immune system with little reliance on cues from the innate response. During the adaptive immune response to a pathogen that has not been encountered before, called a primary response, plasma cells secreting antibodies and differentiated T cells increase, then plateau over time. As B and T cells mature into effector cells, a subset of the naïve populations differentiates into B and T memory cells with the same antigen specificities, as illustrated in [link].

    A memory cell is an antigen-specific B or T lymphocyte that does not differentiate into effector cells during the primary immune response, but that can immediately become effector cells upon re-exposure to the same pathogen. During the primary immune response, memory cells do not respond to antigens and do not contribute to host defenses. As the infection is cleared and pathogenic stimuli subside, the effectors are no longer needed, and they undergo apoptosis. In contrast, the memory cells persist in the circulation.

    The Rh antigen is found on Rh-positive red blood cells. An Rh-negative female can usually carry an Rh-positive fetus to term without difficulty. However, if she has a second Rh-positive fetus, her body may launch an immune attack that causes hemolytic disease of the newborn. Why do you think hemolytic disease is only a problem during the second or subsequent pregnancies?

    If the pathogen is never encountered again during the individual’s lifetime, B and T memory cells will circulate for a few years or even several decades and will gradually die off, having never functioned as effector cells. However, if the host is re-exposed to the same pathogen type, circulating memory cells will immediately differentiate into plasma cells and CTLs without input from APCs or TH cells. One reason the adaptive immune response is delayed is because it takes time for naïve B and T cells with the appropriate antigen specificities to be identified and activated. Upon reinfection, this step is skipped, and the result is a more rapid production of immune defenses. Memory B cells that differentiate into plasma cells output tens to hundreds-fold greater antibody amounts than were secreted during the primary response, as the graph in [link] illustrates. This rapid and dramatic antibody response may stop the infection before it can even become established, and the individual may not realize they had been exposed.

    Vaccination is based on the knowledge that exposure to noninfectious antigens, derived from known pathogens, generates a mild primary immune response. The immune response to vaccination may not be perceived by the host as illness but still confers immune memory. When exposed to the corresponding pathogen to which an individual was vaccinated, the reaction is similar to a secondary exposure. Because each reinfection generates more memory cells and increased resistance to the pathogen, and because some memory cells die, certain vaccine courses involve one or more booster vaccinations to mimic repeat exposures: for instance, tetanus boosters are necessary every ten years because the memory cells only live that long.

    Mucosal Immune Memory

    A subset of T and B cells of the mucosal immune system differentiates into memory cells just as in the systemic immune system. Upon reinvasion of the same pathogen type, a pronounced immune response occurs at the mucosal site where the original pathogen deposited, but a collective defense is also organized within interconnected or adjacent mucosal tissue. For instance, the immune memory of an infection in the oral cavity would also elicit a response in the pharynx if the oral cavity was exposed to the same pathogen.

    Vaccinologist Vaccination (or immunization) involves the delivery, usually by injection as shown in [link], of noninfectious antigen(s) derived from known pathogens. Other components, called adjuvants, are delivered in parallel to help stimulate the immune response. Immunological memory is the reason vaccines work. Ideally, the effect of vaccination is to elicit immunological memory, and thus resistance to specific pathogens without the individual having to experience an infection.

    Vaccinologists are involved in the process of vaccine development from the initial idea to the availability of the completed vaccine. This process can take decades, can cost millions of dollars, and can involve many obstacles along the way. For instance, injected vaccines stimulate the systemic immune system, eliciting humoral and cell-mediated immunity, but have little effect on the mucosal response, which presents a challenge because many pathogens are deposited and replicate in mucosal compartments, and the injection does not provide the most efficient immune memory for these disease agents. For this reason, vaccinologists are actively involved in developing new vaccines that are applied via intranasal, aerosol, oral, or transcutaneous (absorbed through the skin) delivery methods. Importantly, mucosal-administered vaccines elicit both mucosal and systemic immunity and produce the same level of disease resistance as injected vaccines.

    Currently, a version of intranasal influenza vaccine is available, and the polio and typhoid vaccines can be administered orally, as shown in [link]. Similarly, the measles and rubella vaccines are being adapted to aerosol delivery using inhalation devices. Eventually, transgenic plants may be engineered to produce vaccine antigens that can be eaten to confer disease resistance. Other vaccines may be adapted to rectal or vaginal application to elicit immune responses in rectal, genitourinary, or reproductive mucosa. Finally, vaccine antigens may be adapted to transdermal application in which the skin is lightly scraped and microneedles are used to pierce the outermost layer. In addition to mobilizing the mucosal immune response, this new generation of vaccines may end the anxiety associated with injections and, in turn, improve patient participation.

    Primary Centers of the Immune System

    Although the immune system is characterized by circulating cells throughout the body, the regulation, maturation, and intercommunication of immune factors occur at specific sites. The blood circulates immune cells, proteins, and other factors through the body. Approximately 0.1 percent of all cells in the blood are leukocytes, which encompass monocytes (the precursor of macrophages) and lymphocytes. The majority of cells in the blood are erythrocytes (red blood cells). Lymph is a watery fluid that bathes tissues and organs with protective white blood cells and does not contain erythrocytes. Cells of the immune system can travel between the distinct lymphatic and blood circulatory systems, which are separated by interstitial space, by a process called extravasation (passing through to surrounding tissue).

    The cells of the immune system originate from hematopoietic stem cells in the bone marrow. Cytokines stimulate these stem cells to differentiate into immune cells. B cell maturation occurs in the bone marrow, whereas naïve T cells transit from the bone marrow to the thymus for maturation. In the thymus, immature T cells that express TCRs complementary to self-antigens are destroyed. This process helps prevent autoimmune responses.

    On maturation, T and B lymphocytes circulate to various destinations. Lymph nodes scattered throughout the body, as illustrated in [link], house large populations of T and B cells, dendritic cells, and macrophages. Lymph gathers antigens as it drains from tissues. These antigens then are filtered through lymph nodes before the lymph is returned to circulation. APCs in the lymph nodes capture and process antigens and inform nearby lymphocytes about potential pathogens.

    The spleen houses B and T cells, macrophages, dendritic cells, and NK cells. The spleen, shown in [link], is the site where APCs that have trapped foreign particles in the blood can communicate with lymphocytes. Antibodies are synthesized and secreted by activated plasma cells in the spleen, and the spleen filters foreign substances and antibody-complexed pathogens from the blood. Functionally, the spleen is to the blood as lymph nodes are to the lymph.

    Section Summary

    The adaptive immune response is a slower-acting, longer-lasting, and more specific response than the innate response. However, the adaptive response requires information from the innate immune system to function. APCs display antigens via MHC molecules to complementary naïve T cells. In response, the T cells differentiate and proliferate, becoming TH cells or CTLs. TH cells stimulate B cells that have engulfed and presented pathogen-derived antigens. B cells differentiate into plasma cells that secrete antibodies, whereas CTLs induce apoptosis in intracellularly infected or cancerous cells. Memory cells persist after a primary exposure to a pathogen. If re-exposure occurs, memory cells differentiate into effector cells without input from the innate immune system. The mucosal immune system is largely independent from the systemic immune system but functions in a parallel fashion to protect the extensive mucosal surfaces of the body.

    Art Connections

    [link] Which of the following statements about T cells is false?

    1. Helper T cells release cytokines while cytotoxic T cells kill the infected cell.
    2. Helper T cells are CD4+, while cytotoxic T cells are CD8 + .
    3. MHC II is a receptor found on most body cells, while MHC I is a receptor found on immune cells only.
    4. The T cell receptor is found on both CD4 + and CD8 + T cells.

    [link] Based on what you know about MHC receptors, why do you think an organ transplanted from an incompatible donor to a recipient will be rejected?

    [link] MHC receptors differ from person to person. Thus, MHC receptors on an incompatible donor are considered “non-self” and are rejected by the immune system.

    [link] The Rh antigen is found on Rh-positive red blood cells. An Rh-negative female can usually carry an Rh-positive fetus to term without difficulty. However, if she has a second Rh-positive fetus, her body may launch an immune attack that causes hemolytic disease of the newborn. Why do you think hemolytic disease is only a problem during the second or subsequent pregnancies?

    [link] If the blood of the mother and fetus mixes, memory cells that recognize the Rh antigen can form late in the first pregnancy. During subsequent pregnancies, these memory cells launch an immune attack on the fetal blood cells. Injection of anti-Rh antibody during the first pregnancy prevents the immune response from occurring.

    Review Questions

    Which of the following is both a phagocyte and an antigen-presenting cell?

    Which immune cells bind MHC molecules on APCs via CD8 coreceptors on their cell surfaces?

    What “self” pattern is identified by NK cells?

    The acquired ability to prevent an unnecessary or destructive immune reaction to a harmless foreign particle, such as a food protein, is called ________.

    A memory B cell can differentiate upon re-exposure to a pathogen of which cell type?

    Foreign particles circulating in the blood are filtered by the ________.

    Free Response

    Explain the difference between an epitope and an antigen.

    An antigen is a molecule that reacts with some component of the immune response (antibody, B cell receptor, T cell receptor). An epitope is the region on the antigen through which binding with the immune component actually occurs.

    What is a naïve B or T cell?

    A naïve T or B cell is one that has not been activated by binding to the appropriate epitope. Naïve T and B cells cannot produce responses.

    How does the TH1 response differ from the TH2 response?

    The TH1 response involves the secretion of cytokines to stimulate macrophages and CTLs and improve their destruction of intracellular pathogens and tumor cells. It is associated with inflammation. The TH2 response is involved in the stimulation of B cells into plasma cells that synthesize and secrete antibodies.

    In mammalian adaptive immune systems, T cell receptors are extraordinarily diverse. What function of the immune system results from this diversity, and how is this diversity achieved?

    The diversity of TCRs allows the immune system to have millions of different T cells, and thereby to be specific in distinguishing antigens. This diversity arises from mutation and recombination in the genes that encode the variable regions of TCRs.

    How do B and T cells differ with respect to antigens that they bind?

    T cells bind antigens that have been digested and embedded in MHC molecules by APCs. In contrast, B cells function themselves as APCs to bind intact, unprocessed antigens.

    Why is the immune response after reinfection much faster than the adaptive immune response after the initial infection?

    Upon reinfection, the memory cells will immediately differentiate into plasma cells and CTLs without input from APCs or TH cells. In contrast, the adaptive immune response to the initial infection requires time for naïve B and T cells with the appropriate antigen specificities to be identified and activated.

    Glossary


    Specific Defense Mechanism in Human Body | Immunology | Biology

    Specific defense mechanism is the ability of the body to develop immunity against specific pathogens, toxins or foreign things. This is possible by a special immune system that produces antibodies and/or activated lymphocytes that attack and destroy specific invading organisms or toxins. Specific defense mechanisms are also referred to as adaptive or acquired immunity (Table 1).

    Organisms that possess an adaptive immunity also possess innate immunity and many of the mechanisms between the systems are common, so it is not always possible to draw a hard and fast boundary between the individual components involved in each, despite the clear difference in operation. Higher vertebrates and all mammals have both an innate and an adaptive immune system.

    The characteristic features of the adaptive immunity are the following:

    The immune system has the ability to work against specific pathogens.

    It also has the ability to recognise a large number of foreign molecules.

    c. Discrimination between ‘Self’ and ‘Non-Self’:

    The immune system does not normally work against the molecules present in the body. It functions against molecules that are foreign, i.e. ‘non-self’.

    The immune system generates an immune response when the invader or pathogen attacks the body for the first time. This is retained in the memory and if the system encounters the same pathogen for the second time, it is eliminated rapidly offering protection against that particular pathogen.

    The Organs of the Immune System:

    The immune system is made of the primary lymphoid and the secondary lymphoid organs. The primary lymphoid includes the bone marrow and the thymus, while the others such as the spleen, Peyer’s patches of small intestine and the lymph nodes are included in the second category.

    The bone marrow produces B-cells, natural killer cells, granulocytes and immature thymocytes, in addition to red blood cells and platelets. The process of formation of the cells of the immune system is called hematopoiesis. During hematopoiesis, cells differentiate into either mature cells of the immune system or into precursors of cells that migrate out of the bone marrow to continue their maturation elsewhere.

    The function of the thymus is to produce mature T-cells. Immature thymocytese or prothymocytes, leave the bone marrow and migrate into the thymus. The prothymocytes undergo a maturation process, where the cells beneficial to the body are spared, while the cells detrimental to the body are eliminated. The mature T- cells are then released into the blood stream.

    The spleen is the ‘immunological filter’ of the blood. It is a bean-shaped organ. It is made up of B-cells, T-cells, macrophages, dendritic cells, natural killer cells and red blood cells. Old red blood cells are destroyed in the spleen.

    The lymph nodes as small solid structures located at different points along the Lymphatic system. They are the immunologic filters of the lymph. Lymph nodes are located throughout the body. It is composed mostly of T-cells, B-cells, dendritic cells and macrophages. It traps microorganisms and other antigens that enter the lymph or tissue fluid. The trapped antigens are responsible for activation by lymphocytes and initiating immune response.

    e. Mucosal Associated Lymphoid Tissue (MALT):

    These are lymphoid tissue located along the lining of the respiratory, digestive and urinogenital tracts. It constitutes about 50% of the lymphoid tissue in the human body.

    Important Cells of the Immune System:

    The lymphocytes are of two types that are functionally and phenotypically different from each other. They are the T lymphocytes and the B lymphocytes.

    b. Natural Killer Cells or NK Cells:

    NK cells attack cells that have been infected by pathogens, including viruses and cancer cells.

    Macrophages are important in the regulation of immune responses. They are often referred to as scavengers or antigen-presenting cells (APC). They pick up and ingest foreign materials and present these antigens to other cells of the immune system such as T-cells and B-cells. This is one of the important first steps in the initiation of an immune response.

    Dendritic cells, which also originate in the bone marrow, function as antigen presenting cells (APC).

    Types of Specific Defense Mechanisms:

    There are two main types of specific defense mechanisms involved in the immune system:

    a. The Humoral Immune System:

    This system acts against bacteria and viruses in the humour or body liquids such as blood and lymph. The body produces antibody molecules or immunoglobulins in the plasma that can attack the invading agent.

    b. The Cellular Immune System or Cell-mediated Immune System:

    This system takes care of cells that are infected by viruses or cells that are cancerous.


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