T Cell Receptor

Antigens recognized by CD8 or CD4 T clymphocytes have been identified as complexes of short antigenic peptides presented by MHC class I or class molecules. The specificity of antigen recognition is controled by highly variable, clonally distributed heterodimeric αβ T cells receptors (TCR) expressed at the cell surface.

Apart from the structural requirement for binding the TCR to the antigen, many factors, including genetic and structural constraints for TCR expression, positive and negative slection during T cell development in the thymus, and possibly the mode of immunization and stage of resposne may contribute to the selection of an antigen-specific TCR repertoire during an immune response.

Types of TCRs

There are 3 basic types of immune recognition receptors; (1) Antibody/Antigen: The basic structure is an Ig fold which are beta sheets which end up folding into a rigid scaffold. These Ig folds are contained in many immune receptors. Antibodies have 2 Fab arms (light and heavy chain) attached to an Fc arm. (2) Alpha-beta T cell Receptor (TCR): recognize only peptide MHC molecules. The ligand diversity here is limited compared to antibodies. The T cell receptor is analogous to one of an antibody's arms (1 FAB). Combinatorial diversity in the TCR is concentrated into the center of the binding site (CDR3). (3) Gamma-delta T Cell Receptor (TCR): Most peripheral γδ cells are double negative (DN) for CD4 and CD8. Not suprisingly then, they do not comply with the αβ paradigm of MHC recognition.

The four TCR chain gene families (α,β,γ,δ) appear strongly conserved across 400-500 million years of evolution of the jawed vertebrates.

Structure of TCR

αβ TCR

T cells have about 105 TCRs on their surface. A single TCR recognizes an alteration in self-MHC molecules induced by their association with foreign antigens. The majority of T cells express an alpha-beta heterodimer as the antigen binding receptor. (a small yδ- T cells which are generally not MHC restricted, do not express the coreceptors CD4 and CD8 and recognize nonpeptide ligands also exists.) The structure is very similar to that of the immunoglobulins. The alpha chain, like the immunoglobulin L chain, is encoded by V, J, and C gene segments and the beta chain, like the immunoglobulin H chain, is encoded by V, D, J, and C gene segments.

The TCR complex is composed of a clonotypic dimeric TCR, required for antigen recognition, in noncovalent assocation with CD3, a multicomponent signal transduction complex. CD3 consists of 4 different chains. Various other membrane molecules, such as CD4 and CD8, play important accessory roles in antigen recognition and T cell activation.

yδ TCR

A small proportion of T cells express a heterodimer consisting of  delta chains rather than alpha, beta chains. yδ cells make up 2-10% of the total T cell pool in normal human peripheral blood, with the majority expressing the Vy2Vδ2+ TCR (these cells reportedly display principal characgeristics of APC such as DCs. When activated, the efficiently process and sdisplay antigens and provide co-stimulatory signals sufficint for strong induction of naitve alphabeta T cell proliferation and differentiation) . These T cells specfiically recognize small nonpeptide antigens, derived mostly from microbes or nerotic host cells.  Thus certain yδ cells react with antigen that is neither processed nor presented in the context of a MHC molecule. For example, there is a yδ that has been shown to recognize herpes simplex virus-1 glycoprotein I directly. In humans, the main receptor expressed on  delta cells recognizes a microbial phospholipid antigen, 3-formyl-1-butyl pyrophosphate, found on bacteria like M. tuberculosis.

yδ T cells have effector functions similar to alpha-beta T cells in that they have cytolytic activity and cytokine secretion. CD28, the ligand for B7 (CD80/86) and the primary costimulatory for the αβ T cells, is expressed on some γδ cells.

Generation/Development of TCR Diversity

The T cell receptor (TCR) beta chain is formed during T cell development by the recombination of germ line-encoded variable (V)-, diversity (D)-, and joining (J)-region gene elements. The hypervariable region of each TCR Vβ family, or the complementarity-determining region (CDR3) is formed by the joining of the V-(D)-J segments, thereby establishing the diversity of the cellular immune response. Additional diversity is generated within CDR3 through the removal or insertion of non-germ-line nucleotides at each joining junction. Thus, the TCR CDR3 region varies in both length and amino acid sequence.

After transcription of the rearranged TCR genes, RNA processing and translation, the alpha and B chains are expressed as a disulfide linked heterodimer on the membrane of the T cell.

Signal Transduction through TCR

A group of signal tranducing receptors, known as multichain immunoreceptors, have a key role in the development, activation and differentiation of haematopoietic cells. This group comprises the T and B cell receptors, most Fc receptors and the collagen receptor expressed by plalets. Mutlichain immunoreceptors have similar structural and signalling principles in that they consist of a ligand recognition module and non-covalently associated signalling subunits. The hallmark of the cytoplasmic domain of the signaling subunits is the presence of at least one immunreceptor tyrosine-based activation motif (ITAM).

Following the interaction of the recognition unit with its cognate ligand, the connection between the engaged receptor and the intracellular environment is initiated by phosphorylation of two core tyrosine residues within the ITAMs of the signal transducing subunits. This is achieved by tyrosine kinases (PTKs) of the SRC-Kinase family, such as LCK and FYN in the case of T cells and NK cells.

When the TCR encounters antigen on an infected cell, a signal is sent into the cell via sequential tyrosine phsophorylation of key TCR-associated signalling molecules. This signal initiates formation of an immunologic synapse betweent he T cell and its target. The TCR CD3 complex, CD28 and associated signaling molecules cluster in the center of the synapse. The synapse forms within minutes of TCR engagement and lasts for more than an hour until the entire TCR complex is internalized.

  Nature Reviews Immunology 4, 603-616 (2004)