Microorganisms and viruses that penetrate cells and multiply within them are out of reach of antibodies. T cells are equipped to deal with this need. On their cell surfaces are dedicated T-cell receptors (TCRs) that, like antibodies, show very high specificity in recognizing and binding sequences from foreign antigens. The TCRs are structurally and evolutionarily related to Igs (see Figure 1).
Fig1. The immunoglobulin superfamily. The immunoglobulin (Ig) domain is a barrel-like structure held together by a disulfide bond (red dot). As shown here, multiple copies of the Ig domain are found in many proteins with important immune system functions—the pale orange boxes show variable domains. Note that immunoglobulins have essentially the same structure as the B-cell receptor (they differ by lacking membrane-binding sequences near the end of the constant region). TCR, T-cell receptor; β2 M, β2-microglobulin.
TCRs are heterodimers and come in two classes. The vast majority have α and β chains (αβ TCRs); a few have γ and δ chains (γδ TCRs). Unlike the immunoglobulins of B cells, which can collectively recognize foreign antigens on a wide range of different molecular classes, TCRs are especially focused on protein antigens (the predominant αβ TCRs are limited to recognizing protein components).
There are three major classes of T cells with αβ TCRs—killer (cytotoxic) T cells, helper T cells, and regulatory T cells—and individual αβ T cells that have previously encountered foreign antigen can be stimulated to undergo clonal expansion (Table1).
Table1. CLASSES OF T CELLS WITH αβ T-CELL RECEPTORS THAT BIND MHC–PEPTIDE ANTIGENS
Although αβ TCRs recognize protein components, they do so only after the proteins have been degraded inside cells, whereupon the resulting peptides are individually bound by a newly made major histocompatibility complex (MHC) protein. Holding the peptide in a cleft, an MHC protein transports it to the surface of the cell.
Antigen presentation
After a peptide has been bound by an MHC molecule and then transported with it to the cell surface, the MHC protein–peptide complex acts as a signal for a T cell with an αβ TCR that can specifically bind it. That is, an MHC protein is required to present a peptide on the cell surface so that it can be recognized by a T cell with the appropriate αβ TCR (antigen presentation). T-cell receptors on killer (cytotoxic) T cells recognize class I MHC–peptide signals, and those on helper T cells recognize class II MHC– peptide signals, but additional types of receptor–signal interactions are also required (Figure 2A and B).
Fig2. Antigen presentation. (A) Differential recognition of class I and class II MHC–peptide signals. For killer (cytotoxic) T cells, the T-cell receptor recognizes a class I MHC–peptide signal, but on helper T cells it recognizes a class II MHC protein–peptide signal. (B) Different types of receptors on the T cell are required to recognize signals on the antigen-presenting cell. Here we illustrate the example of a professional antigen-presenting cell presenting a class II MHC–peptide signal to be recognized by a T-cell receptor on a helper T cell. In addition, a CD8 protein on the helper T cell is required to bind a nonpolymorphic component of the class II MHC protein, and a co-stimulatory signal molecule, such as a member of the B7 family, needs to be recognized by CD28 receptors on the T-cell surface. Cell adhesion is promoted by, for example, using an LFA1 receptor on the T cell to recognize an ICAM signal on the presenting cell. (C) MHC restriction. T cells have cell-specific receptors that recognize a combination of a specific peptide and a specific MHC protein. In this case, we imagine a human T cell whose receptor is specific for a combination of peptide X and a class I MHC allele, HLA-A1. (Adapted from Murphy K & Weaver C [2016] Janeway’s Immunobiology, 9th edn. Garland Science. With permission from WW Norton.)
Because class I MHC–peptide signals are expressed on almost all nucleated cells, almost any cell has the potential to present antigen to a killer T cell. However, class II MHC proteins are expressed on a very limited set of cells, notably dendritic cells, macrophages, and B cells. These cells are very active in presenting antigens to helper T cells and are often described as “professional” antigen-presenting cells.
From antigen presentation to T-cell activation
In addition to MHC–peptide signals, co-stimulatory molecules on the surface of an antigen-presenting cell interact with specific receptors on T cells (see Figure 2B). The co-stimulatory signal delivered to helper T cells is crucially important in inducing them to synthesize interleukin-2 (IL-2; a T-cell growth factor) and to express high-affinity receptors for IL-2. The secreted IL-2 stimulates proliferation of T cells expressing the CD4 or CD8 cell surface receptors. This complex way of inducing T-cell responses is presumably necessary to avoid inadvertent (and potentially damaging) activation of T cells, and to carefully regulate T-cell proliferation and differentiation.
Co-stimulatory molecules are so critically important for initiating and regulating immune responses that they are not constitutively expressed, even by professional antigen-presenting cells. Their expression can be induced via the TCR-triggered transient expression of CD40 ligand on T cells and the subsequent interaction with, and cross-linking of this ligand to, CD40 on professional antigen-presenting cells. Expression of co-stimulatory molecules is also triggered by signaling arising from the recognition of the conserved features of pathogens that is part of the innate immune system, most importantly the signaling through Toll-like receptors expressed on dendritic cells, macrophages, and certain other cells.
MHC restriction
The process whereby αβ T cells recognize protein antigens only after they have been degraded to form peptides that become associated with MHC molecules is described as MHC restriction. Note that it is the combination of a specific MHC protein and a specific peptide that an αβ T-cell receptor recognizes (Figure 2C). The MHC protein must be a self-MHC protein, one that is expressed naturally by host cells (which is why organ trans plantation usually provokes strong immune responses in the recipient—MHC molecules on the transplanted tissue are treated as being foreign proteins).
Because all proteins in a cell routinely undergo degradation in proteasomes, MHC restriction allows T cells to survey a peptide library derived from the entire set of proteins contained within a presenting cell, but which is presented on the surface of the cell by MHC molecules. As a result, MHC restriction provides a remarkable evolutionary solution to the problem of how to detect intracellular pathogens. At the same time, it restricts T cells to recognizing only those antigens that are associated with host-cell MHC molecules and that are derived from intracellular spaces. T cells therefore complement B cells and antibodies, which can only recognize extracellular antigens and pathogens.
The need for self-tolerance
An important aspect of antigen presentation is that MHC proteins cannot distinguish self- from nonself-antigens, and therefore, except on the rare occasions when a cell does indeed become infected or captures a microbial protein, the MHC proteins on its surface are presenting peptides derived from the degradation of self-proteins. To avoid widespread attack of body cells by T cells, a self-tolerance mechanism is established during the development of αβ T cells in the thymus: only those T cells that have receptors that potentially recognize foreign peptides in association with self-MHC molecules are allowed to mature and are released into the periphery ( positive selection). Those that recognize self-peptides are induced to commit suicide by apoptosis ( negative selection).
