Helper T Cells and Their Response to Antigen



Helper T Cells and Their Response to Antigen



Key Points



• Helper T cells express antigen receptors (TCRs) consisting of paired peptide chains, either α and β or γ and δ.


• These paired chains form antigen-binding receptors whose ligands are peptides linked to major histocompatibility complex (MHC) molecules on antigen-presenting cells.


• The antigen-binding chains of the TCR connect to a complex signal transducing component called CD3.


• Each TCR is also associated with either CD4 or CD8. CD4 binds to MHC class II molecules on antigen-presenting cells. CD8 binds to MHC class I molecules expressed on all nucleated cells.


• To respond to antigens, T cells must bind to antigenic peptides linked to MHC molecules. They must also receive co-stimulation from cytokines and other molecules.


• The multiple signals sent by an antigen-presenting cell are communicated to a T cell through an immunological synapse.


• There are three major subpopulations of helper T cells. Th1 cells are stimulated by interleukin-12 (IL-12) and secrete interferon-γ (IFN-γ) in response. They generally promote cell-mediated responses.


• Th2 cells secrete IL-4, 1L-13, and IL-10. They generally promote antibody responses.


• Th17 cell development is stimulated by IL-6, TGF-β, and IL-23. They secrete IL-17 and promote neutrophil-mediated inflammation.


• α/β Helper T cells are the predominant T cells in most mammals. γ/δ Helper T cells are mainly confined to the intestinal wall in humans but are the predominant circulating T cells in young ruminants and pigs.


Unlike the innate immune responses that are triggered by a limited number of molecular patterns restricted to the major groups of microorganisms, the lymphocytes of the adaptive immune system are able to recognize and respond to “everything,” or at least to a large number of very diverse foreign antigens. These lymphocytes have receptors that bind specific antigens and, under the right conditions, respond by mounting cell-mediated or antibody-mediated immune responses.


There are four major populations of lymphocytes with antigen-binding receptors. These include helper T cells that regulate immune responses; effector or cytotoxic T cells that destroy cells expressing endogenous antigens; regulatory T cells that control everything, and B cells that produce antibodies. Each of these cell populations can trigger an immune response only when antigens bind to their specific receptors. This chapter discusses the first of these major lymphocyte populations, the helper T cells.


Exogenous antigen is trapped and processed by dendritic and other antigen-presenting cells and then presented to helper T cells. Each T cell is covered by thousands of identical antigen receptors. If these receptors bind antigen in the correct manner, the helper T cell is activated and initiates an immune response by secreting cytokines, dividing, and differentiating. As you will see later, the other antigen-responsive cell populations, the B cells and the cytotoxic T cells, cannot respond to antigens unless they too are stimulated by helper T cells. Because of the central role of helper T cells, they must be carefully regulated through cell-cell interactions and by the activities of many different cytokines.


It is important to point out at this stage that the antigen receptors on T cells do not develop in order to bind to specific foreign antigens. On the contrary, these antigen receptors are generated randomly. As a result, the antigen receptors on all the T cells in the body form a large diverse repertoire. It may be expected that any foreign antigen that enters the body will encounter and bind to at least one T cell. Because each T cell has a single receptor specificity, the repertoire of receptors is, in effect, the repertoire of the T cells. T cell antigen receptors recognize the complexes formed between antigens and MHC molecules. They cannot recognize or respond to free antigen molecules.


Given the random nature of receptor binding, the strength of binding (or affinity) between an antigen and its receptors will vary. Thus an antigen may be bound strongly by some receptors and weakly by others. If this binding strength is very weak, the encounter between the antigen and its receptor may be insufficient to activate the T cell.


In a newborn animal that has never previously encountered antigens, the number of T cells that can bind any specific antigen may be very low. To increase the probability of an antigen encountering a T cell with the correct receptor, the T cells are concentrated in secondary lymphoid organs such as lymph nodes, where their chances of a successful interaction with antigen-bearing dendritic cells are maximized. In primed animals in which mature T cells are plentiful, they can migrate into the tissues, where they can encounter other antigen-presenting cells, such as macrophages, and B cells.



Immunoglobulin Superfamily


Proteins are constructed by linking together multiple peptide modules or domains. Each domain usually has a specialized function. For example, in proteins located on a cell surface, the membrane-binding domain contains hydrophobic amino acids that can penetrate cell membrane lipid bilayer. Other domains may be responsible for the structural stability of a protein or for its biological activities. In antibody (immunoglobulin) molecules, one domain is used to bind antigen, and other domains are responsible for cell binding. The presence of similar domains in dissimilar proteins suggests that they have a common origin, and proteins may be classified into families or superfamilies based on their domain structure.


Proteins belonging to the immunoglobulin superfamily play key roles in immunity. The members of this superfamily all contain at least one immunoglobulin domain. In a typical immunoglobulin domain, the peptide chains weave back and forth to form a pleated sheet that folds into a sandwich-like structure. Immunoglobulin domains were first identified in antibody molecules (immunoglobulins). They have since been found in many other proteins, and collectively these proteins form the immunoglobulin superfamily. The superfamily includes some proteins with multiple immunoglobulin domains and some with only a single domain. Important proteins with multiple domains include the B cell antigen receptors (BCRs), the T cell antigen receptors (TCRs), and the MHC class I and II molecules (Figure 14-1). All of the members of this superfamily are receptors, most are found on cell surfaces, and none has enzymatic activity. Many cellular responses are triggered by interactions between two different members of the superfamily as, for example, between TCR and MHC molecules.


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FIGURE 14-1 The four key antigen receptors of the immune system—TCR, MHC class I, MHC class II, BCR—are each constructed using immunoglobulin domains as building blocks. Each binds antigen through the use of variable domains. All are members of the immunoglobulin superfamily.


T Cell Antigen Receptor


Antigen-Binding Component


Each T cell has about 30,000 identical antigen receptors (TCRs) on its surface. Each TCR is a complex structure containing multiple glycoprotein chains. Two of these chains are paired to form the antigen-binding site; the other chains transmit the signal generated by antigen binding to the cell. Two different types of TCR have been identified based on the paired peptide chains used for antigen binding (Figure 14-2). One type employs γ and δ (γ/δ) chains. The other employs α and β (α/β) chains. In humans, mice, and probably most nonruminants, 90% to 99% of T cells use α/β receptors. In calves, lambs, and piglets in contrast, up to 66% of T cells may use γ/δ receptors.


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FIGURE 14-2 T cells can be divided into many different subpopulations based on the antigen receptors they employ, on the accessory molecules that support their activity, and ultimately on their functions.

The four antigen-binding chains (α, β, γ, δ) are similar in structure, although they differ in size. Thus the α chain is 43 to 49 kDa, the β chain is 38 to 44 kDa, the γ chain is 36 to 46 kDa, and the δ chain is 40 kDa. Size differences are due to variations in glycosylation. Each of these chains is formed from four domains (Figure 14-3). The N-terminal domain contains about 100 amino acids whose sequence varies greatly among cells. This is therefore called the variable (V) domain. The second domain contains about 150 amino acids. Its amino acid sequence does not vary, so it is called the constant (C) domain. The third, very small domain consists of 20 hydrophobic amino acids passing through the T cell membrane. The C-terminal domain within the cytoplasm of the T cell is only 5 to 15 amino acids long. The paired chains are joined by a disulfide bond between their constant domains to form a stable heterodimer. As a result, the two V domains form a groove in which antigens and MHC molecules bind. The precise shape of this antigen-binding groove varies among different TCRs because of the variable amino acid sequences in the V domains. The specificity of the binding between a TCR and an antigen is determined by the shape of the groove formed by the V domains.


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FIGURE 14-3 Schematic diagram showing the domain structure of the two peptide chains that make up the antigen-binding component of an α/β TCR.

When the V domains are examined closely, it is found that within each V domain is a region where the amino acid sequence is especially highly variable. This is the region that actually comes into contact with the antigen. For this reason, it is called the hypervariable or the complementarity determining region (CDR). The antigen-binding site of the TCR is formed by the paired CDRs that line the groove. The rest of each V domain outside the CDRs has a constant sequence and is called the framework region.



Signal Transduction Component


CD3 Complex


The binding of antigen to the TCR sends a signal to trigger the T cell response. The two antigen-binding chains of each TCR are associated with a cluster of signal transducing proteins called the CD3 complex (Figure 14-4). The CD3 complex consists of five chains (γ, δ, ε, ζ, and η) (Table 14-1) arranged as three dimers γ-ε, δ-ε, and either ζ-ζ or ζ-η. The TCR β chain is linked to the γ-ε dimer, and the TCR α chain is linked to the δ-ε dimer. About 80% of α/β TCRs contain a ζ-ζ homodimer, so that the complete complex consists of αβ-γε-δε-ζζ. The remaining 20% contain ζ-η heterodimers (they therefore consist of αβ-γε-δε-ζη).



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FIGURE 14-4 Overall structure of the TCR/CD3 complex. The signal transduction proteins are collectively classified as CD3. About 80% of α/β TCRs use ζζ dimers. The remaining 20% use ηζ heterodimers. Most γ/δ TCRs probably use a completely different signal transduction complex.


CD4 and CD8


Two other proteins closely associated with the TCR are CD4 and CD8. CD4 is a single-chain glycoprotein of 55 kDa, and CD8 is a dimer of 68 kDa. (One chain of CD8 is called α, the other is β. In humans, pigs, mice, and cats, CD8 is an α-β heterodimer or, less commonly, an α-α homodimer.) Both CD4 and CD8 are members of the immunoglobulin superfamily. The presence of CD4 or CD8 determines the class of MHC molecule that is recognized by the T cell (Figure 14-5). For example, CD4, found only on helper T cells, binds MHC class II molecules on antigen-presenting cells. CD8, in contrast, is found only on cytotoxic T cells and binds MHC class Ia molecules on virus-infected or other abnormal cells. CD4 and CD8 enhance TCR signal transduction 100-fold when they cross-link to an MHC molecule on an antigen-presenting cell.


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FIGURE 14-5 Role of CD4 and CD8 in promoting T cell responses. These molecules link the T cell to the antigen-presenting cell, binding the two cells together and ensuring that an effective signal is transmitted between them. CD4 binds to MHC class I molecules. This interaction is seen in Figure 10-6, A.


Co-stimulators


The binding of a TCR to a peptide-MHC complex is not sufficient by itself to trigger helper T cell differentiation. Additional signals acting through multiple pathways are needed for the cell to fully differentiate. For example adhesion molecules must bind the T cells and antigen-presenting cells firmly together and thus permit prolonged, strong signaling between the cells. TCR-antigen binding then triggers the initial steps. Ligands such as CD40 on antigen-presenting cells bind to T cells and amplify their responses. T cells are also stimulated by cytokines secreted by the antigen-presenting cells. These determine the way in which a T cell responds to antigen, turning on some pathways and turning off others.



Co-stimulatory Receptors


Several additional receptors must be stimulated in order to activate T cells.



CD40-CD154 Signaling


CD40 is a receptor expressed on antigen-presenting cells. Its ligand is CD154, a protein expressed on helper T cells several hours after their TCRs have bound antigen (Figure 14-6). When CD154 and CD40 bind, signals are sent in both directions. The signal from the antigen-presenting cell to the T cell causes it to express a receptor called CD28. The signal from the T cell to the antigen-presenting cell stimulates it to express either CD80, or CD86. CD40-CD154 signaling also stimulate the antigen-presenting cell to secrete multiple cytokines, including interleukin-1 (IL-1), IL-6, IL-8, IL-12, CCL3, and tumor necrosis factor-α (TNF-α).


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FIGURE 14-6 Antigen-presenting cells and helper T cells engage in a dialog. Thus binding of antigen to the TCR causes the T cell to express CD40 ligand (CD154). This engages CD40 on the antigen-presenting cell. As a result, CD28 and CD152 are expressed on the T cell, and CD80 or CD86 is expressed on the antigen-presenting cell. Depending on which receptors are engaged, the T cell may be stimulated or suppressed.
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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Helper T Cells and Their Response to Antigen

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