For instance, rag-deficient mice are devoid of T and B lymphocytes. Indeed, the importance of receptor diversification is apparent in murine models and in a number of primary immunodeficiencies in humans. 6 Moreover, gene rearrangement provides the T cell compartment with sufficient diversity to sustain protective immunity. Expression of RAG1 and RAG2 is lymphoid-specific and dictates irreversible T cell lineage commitment in developing thymocytes. Gene rearrangement is an essential event in the life of a T cell. The intervening sequences are then spliced out, generating a TCR-β transcript in which, V, D, J and C segments are directly adjacent. V to DJ recombination subsequently brings the rearranged DJ join to one of many TRBV segments. D to J recombination occurs first, juxtaposing TRBD1 to one of the six TRBJ1 segments or TRBD2 to one the seven TRBJ2 segments. VDJ recombination is a two-step, ordered process. The trb locus is composed of a 5′ V cluster (48 TRBV gene segments) followed by two 3′ TRBD–TRBJ–TRBC clusters. The intervening sequences are spliced out, producing a TCR-α transcript in which V, J and C segments are directly adjacent. V to J recombination brings together one of many TRAV segments to one of many TRAJ segments. TCR-δ D and J segments (TRDD and TRDJ, respectively) are also present in the locus. The tra locus (in which the TCR-δ, or trd locus is also embedded) comprises a 5′ V gene segment cluster (46 TRAV segments) followed by a central J cluster (51 TRAJ segments) and a single C gene segment (TRAC). In contrast, the CDR3 loops are the product of junctional diversity and are consequently hypervariable ( Figure 1b). The process of V (D) J recombination is such that CDR1α, CDR1β, CDR2α and CDR2β are entirely encoded in germline DNA segments. TCR chains are assembled somatically during T cell development by the joining of discrete V, (D) and J gene segments by recombination activating gene (RAG)1 and RAG2 ( Figures 1b and 2). Diversity in the TCR is predominantly confined to six hypervariable hairpin loops in the variable domains, called complementarity-determining regions 5 (CDR) ( Figure 1a). 3, 4 Each TCR chain is composed of a constant and a variable domain, followed by a membrane-spanning region and a short cytosolic tail. The TCR is a heterodimer of one α and one β chain, or one γ and one δ chain, which are disulphide-linked. In the steady state, homeostasis of T cell numbers is also MHC-dependent. 1 In secondary lymphoid organs, ligation of the TCR to pMHC provides the cell with the earliest signals required for the execution of a complex differentiation programme associated with effector function. In the thymus, T cell signalling induced by self-pMHC engagement contributes to the process of selection at the double-positive stage, whereby only a fraction of thymocytes bearing TCRs within a narrow affinity range are permitted to differentiate into mature T cells. The T cell receptor (TCR) is the fundamental unit underlying all peptide-MHC (pMHC) recognition events. T cells orchestrate immune responses by interrogating protein expression via peptides cradled in major histocompatibility complex (MHC) molecules at the cell surface. Finally, we suggest that with the development of high-throughput sequencing, common TCR ‘signatures’ raised against specific antigens could provide important diagnostic biomarkers and surrogate predictors of disease onset, progression and outcome. We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires. Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease. However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains. It is widely assumed that TCR diversity is required, or at least highly desirable, to provide sufficient immune coverage. Interaction between peptide-MHC (pMHC) and the T cell receptor (TCR) is central to both thymic selection and peripheral antigen recognition. It has been known for several decades that T lymphocytes recognize short peptides derived from degraded proteins presented by major histocompatibility complex (MHC) molecules at the cell surface. T and B lymphocytes are indeed truly unique in their ability to generate receptors capable of recognizing virtually any pathogen. The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system.
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