TCRs recognize peptides displayed by MHC molecules

T cells generally recognize fragments of degraded proteins (peptides), which must be bound to (‘presented by’) specialized antigen-presenting molecules encoded by the major histocompatibility complex (MHC). In humans the MHC was first identified as the human leukocyte antigen (HLA) locus so the molecules may also be called HLA molecules.

MHC molecules can display a wide range of peptides, which have been derived from intracellular proteins, on the cell surface thereby alerting the immune system to the presence of intracellular invaders.

Because MHC molecules are expressed only on the cell surface, engagement of the TCR occurs only in the context of intimate cell–cell interactions.

When a primed T cell bearing an appropriate TCR (capable of recognizing, for example, a particular viral peptide) comes into contact with an infected cell, it can rapidly kill that cell and thereby limit the spread of the viral infection.

The requirement for cell–cell interaction also allows T cells to provide critical regulatory functions. T cells, for example, can couple signals from the innate immune system, such as those arising from ‘professional’ APCs (e.g. dendritic cells) with adaptive (T and B cell) responses, providing a critical layer of integration, coordination, and regulation.

TCRs are similar to immunoglobulin molecules

The TCR was identified much later than immunoglobulin, even though early theoretical considerations strongly suggested that T cells must bear cell surface antigen receptors. It is now clear that there are two varieties of TCR, termed αβ and γδ, and that both molecules:

Fig. 5.1 Similarities and differences between T cell receptors and immunoglobulins

TCRs are very similar to Fab fragments of B cell receptors. Both receptor types are composed of two different peptide chains and have variable regions for binding antigen, constant regions, and hinge regions. The principal differences are that TCRs remain membrane-bound and contain only a single antigen-binding site.

The two types of TCR tend to populate different tissue sites and are thought to perform distinct functions.

The αβ heterodimer is the antigen recognition unit of the αβ TCR

The αβ TCR is the predominant receptor found in the thymus and peripheral lymphoid organs of mice and humans. It is a disulfide-linked heterodimer of α (40–50 kDa) and β (35–47 kDa) subunits and its structural features have been determined by X-ray crystallography (Fig. 5.2).

Fig. 5.2 The T cell antigen receptor

Three-dimensional structure of an αβ TCR – only extracellular domains are shown. The α chain is colored blue (residues 1–213), and the β chain is colored green (residues 3–247). The β strands are represented as arrows and labeled according to the standard convention used for the immunoglobulin fold. The disulfide bonds (yellow balls for sulfur atoms) are shown within each domain and for the C terminal interchain disulfide. The complementarity determining regions (CDRs) lying at the top of the diagram are numerically labeled (1–4) for each chain. These form the binding site for antigen/MHC molecule.

(Adapted from Garcia KC, Degano M, Stanfield RL, et al. Science 1996;274:209–219. Copyright AAAS.)

Each polypeptide chain of the αβ TCR contains two extracellular immunoglobulin-like domains of approximately 110 amino acids, anchored into the plasma membrane by a transmembrane domain that has a very short cytoplasmic tail.

The extracellular portions of the α and β chains fold into a structure that resembles the antigen-binding portion (Fab) of an antibody (see Fig. 3.9). Indeed, as in antibodies, the amino acid sequence variability of the TCR resides in the N terminal domains of the α and β (and also the γ and δ) chains.

The regions of greatest variability correspond to immunoglobulin hypervariable regions and are also known as complementarity determining regions (CDRs). They are clustered together to form an antigen-binding site analogous to the corresponding site on antibodies (see Fig. 5.2). Note, however, that:

The disulfide bond that links the α and β chains is in a peptide sequence located between the constant domain of the extracellular portion of the receptor and the transmembrane domain (shown as the C terminal residue in the α and β chain in Fig. 5.2).

One remarkable feature of the transmembrane portion of the receptor is the presence of positively charged residues in both the α and β chains. Unpaired charges would be unfavorable in a transmembrane segment. Indeed, these positive charges are neutralized by assembly of the complete TCR complex, which contains additional polypeptides bearing complementary negative charges (see below).

The CD3 complex associates with the antigen-binding αβ or γδ heterodimers to form the complete TCR

The αβ or γδ heterodimers must associate with a series of polypeptide chains collectively termed the CD3 complex for the antigen-binding domains of the TCR to form a complete, functional receptor that is stably expressed at the cell surface and is capable of transmitting a signal upon binding to antigen.

The four members of the CD3 complex (γ, δ, ε, and ζ) are sometimes termed the invariant chains of the TCR because they do not show variability in their amino acid sequences. (The γ and δ chains of the CD3 complex should not be confused with the quite distinct antigen-binding variable chains of the TCR that bear the same names.)

The CD3 chains are assembled as heterodimers of γε and δε subunits with a homodimer of ζ chains, giving an overall TCR stoichiometry of (αβ)₂, γ, δ, ε₂, ζ₂. Current data suggest that the TCR complex exists as a dimer (Fig. 5.3).

Fig. 5.3 The T cell receptor complex

The TCR α and β (or γ and δ) chains each comprise an external V and C domain, a transmembrane segment containing positively charged amino acids, and a short cytoplasmic tail. The two chains are disulfide linked on the membrane side of their C domains. The CD3 γ, δ, and ε chains comprise an external immunoglobulin-like C domain, a transmembrane segment containing a negatively charged amino acid, and a longer cytoplasmic tail. A dimer of ζζ, ηη, or ζη is also associated with the complex. Several lines of evidence support the notion that the TCR–CD3 complex exists at the cell surface as a dimer. The transmembrane charges are important for the assembly of the complex. A plausible arrangement that neutralizes opposite charges is shown.

The CD3 γ, δ, and ε chains are the products of three closely linked genes, and similarities in their amino acid sequences suggest that they are evolutionarily related.

Indeed, all three are members of the immunoglobulin superfamily, each containing an external domain followed by a transmembrane region and a substantial, highly conserved, cytopasmic tail of 40 or more amino acids.

As with the transmembrane domains of the variable chains of the TCR, the membrane-spanning regions of these CD3 chains contain charged amino acids.

The negatively charged residues in the transmembrane region of the CD3 chains interact with (and neutralize) the positively charged amino acids in the αβ polypeptides, leading to the formation of a stable TCR complex (see Fig. 5.3).

The CD3ζ gene is on a different chromosome from the CD3γδε gene complex, and the ζ protein is structurally unrelated to the other CD3 components. The ζ chains possess:

An alternatively spliced form of CD3ζ, called CD3η, possesses an even larger cytoplasmic tail (42 amino acids longer at the C terminus).

The γδ TCR structurally resembles the αβ TCR but may function differently

The overall structure of the γδ TCR is similar to that of its αβ counterpart. Each chain is organized into:

One indication that the two types of T cell (i.e. T cells with αβ TCRs and T cells with γδ TCRs) might perform different functions comes from their anatomic distribution:

It is further believed that there are distinct subsets of γδ T cells that can perform different functions.

TCR variable region gene diversity is generated by V(D)J recombination

As with antibody genes, a highly diverse repertoire of TCR variable region genes is generated during T cell differentiation by a process of somatic gene rearrangement termed V(D)J recombination (see Chapter 3). Variable (V), joining (J), and sometimes diversity (D) gene segments are joined together to form a completed variable region gene.

Junctional diversity (imprecise joining of V, D, and J with loss and/or addition of nucleotides) contributes an enormous amount of variability to the TCR repertoire in addition to the variation that results from combinatorial assortment of the various gene segments.

TCRs are encoded by several sets of genes

The general arrangement of the genes encoding the α, β, γ, and δ chains of the TCR is remarkably similar to that of the immunoglobulin heavy chain genes (see Figs 3.21–3.23), suggesting a common origin from a primordial rearranging antigen receptor locus.

Figure 5.w1 illustrates the murine TCR genes, which are similar to those of humans. All four TCR gene families have been strongly conserved across more than 400 million years of evolution of the jawed vertebrates, which suggests a strong selective pressure for the preservation of both αβ and γδ T cell functions.

Fig. 5.w1 Murine T cell recpetor genes

The δ chain loci are embedded within the α loci and tandem duplication has occurred in the β chain loci. The last of each set of Jβ genes and the Vγ3 gene are pseudogenes.

The nomenclature of the TCR genes is simple – the TCRA locus encodes the α gene, TCRB the β gene, and so on. Interestingly, the TCRD locus is nested within the TCRA cluster.

The α and γ loci have sets of V and J gene segments (analogous to immunoglobulin light chain loci), whereas the β and δ loci have V, D, and J gene segments (analogous to immunoglobulin heavy chains).

TCR V genes used in the responses against different antigens

A major area of research in recent years has been to determine which sets of TCR V genes are used in the responses against different antigens. Because T cells recognize antigenic peptides bound to a particular MHC molecule this depends on:

Once the TCRs have been generated, T cells are subjected to thymic selection and may be further selected by interactions with APCs in the periphery. For these reasons, even if TCRs are generated by random recombination of gene segments, the expressed repertoire will be skewed toward the use of particular gene segments. Furthermore, the preference for different V gene segments by distinct T cell subsets may reflect their ontogeny. For example:

It is thought that these populations arise at distinct stages of intrathymic T cell development, and they appear to have distinct functions.

Recognition by the αβ TCR requires antigen to be bound to an MHC molecule

As discussed in Chapter 3, antibodies recognize intact proteins, binding either to linear epitopes derived from contiguous amino acids or discontinuous epitopes produced by amino acids that are not near one another in the primary structure but are brought together in the three dimensional structure of the protein. In contrast, T cell receptors only recognize linear epitopes present in the form of short peptides which are generated by degradation of intact proteins within the cell (a process termed antigen processing). This property of T cell receptors is critical to the way the immune system recognizes intracellular pathogens and tumor antigens. Such antigens present a special challenge to the immune system: intracellular antigens are hidden within the cell, and are not available for recognition by antibodies. How can intracellular antigens be recognized by extracellular receptors? The immune system has solved this problem by evolving an elegant means of displaying internal antigens (including those of intracellular pathogens) on the cell surface, allowing their recognition by T cells:

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