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Review
. 2015 Jul;12(4):391-9.
doi: 10.1038/cmi.2014.134. Epub 2015 Jan 26.

αβ T Cell Receptors as Predictors of Health and Disease

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Free PMC article
Review

αβ T Cell Receptors as Predictors of Health and Disease

Meriem Attaf et al. Cell Mol Immunol. .
Free PMC article

Abstract

The diversity of antigen receptors and the specificity it underlies are the hallmarks of the cellular arm of the adaptive immune system. T and B lymphocytes are indeed truly unique in their ability to generate receptors capable of recognizing virtually any pathogen. 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. Interaction between peptide-MHC (pMHC) and the T cell receptor (TCR) is central to both thymic selection and peripheral antigen recognition. It is widely assumed that TCR diversity is required, or at least highly desirable, to provide sufficient immune coverage. However, a number of immune responses are associated with the selection of predictable, narrow, or skewed repertoires and public TCR chains. Here, we summarize the current knowledge on the formation of the TCR repertoire and its maintenance in health and disease. We also outline the various molecular mechanisms that govern the composition of the pre-selection, naive and antigen-specific TCR repertoires. 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.

Figures

Figure 1
Figure 1
TCR protein and gene structure. (a) Structure of the AS01 TCR. The TCR-α and TCR-β CDR loops are short hairpin turns linking adjacent β-strands. (b) CDR1 and CDR2 are entirely encoded in the germline V genes, whereas CDR3 lies at the junction between the rearranged V and J segments (TCR-α) and V, D and J segments (TCR-β). The CDR3 junctional sites are assembled by random addition and deletion of template and non-template nucleotides (blue for TCR-α and orange for TCR-β). CDR, complementarity-determining region; TCR, T cell receptor.
Figure 2
Figure 2
Gene rearrangement at the tr loci. (a) VJ recombination at the tra 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). TCR-δ D and J segments (TRDD and TRDJ, respectively) are also present in the locus. V to J recombination brings together one of many TRAV segments to one of many TRAJ segments. The intervening sequences are spliced out, producing a TCR-α transcript in which V, J and C segments are directly adjacent. (b) VDJ recombination at the trb locus. The trb locus is composed of a 5′ V cluster (48 TRBV gene segments) followed by two 3′ TRBD–TRBJ–TRBC clusters. VDJ recombination is a two-step, ordered process. D to J recombination occurs first, juxtaposing TRBD1 to one of the six TRBJ1 segments or TRBD2 to one the seven TRBJ2 segments. V to DJ recombination subsequently brings the rearranged DJ join to one of many TRBV segments. The intervening sequences are then spliced out, generating a TCR-β transcript in which, V, D, J and C segments are directly adjacent. TCR, T cell receptor.
Figure 3
Figure 3
Size and composition of the pre-selection, naive and antigen-experienced repertoires. TCR diversity is greatest in the pre-selection repertoire (gray). Positive and negative selection in the thymus purges the pre-selection repertoire of most specificities, creating a peripheral naive repertoire that is substantially less diverse (green). In the periphery, antigen exposure further narrows the repertoire over time leading to clonal expansion of antigen-specific populations (blue). TCR diversity is largely preserved throughout the human lifespan, except in infancy and old age, but the net distribution of TCR clonotypes is altered. TCR, T cell receptor.
Figure 4
Figure 4
Skewing of the TCR repertoire in human disease. The peripheral TCR repertoire is shaped by antigen encounter and altered in the context of disease. Classical pMHC recognition leads to clonal expansion of antigen-specific T cells, which in some human pathologies can lead to extreme oligoclonality and skewing (top). In this setting, the expansion of public clonotypes can be beneficial as seen in HIV-1 infection, but in other cases, certain clonotypes are involved in disease pathogenesis as described for MS. Other semi-invariant clonotypes such as iNKT (also called NKT type I), MAIT and GEM TCRs expand in response to some microbial infections in an HLA-independent manner (centre). Some malignancies such as ALL, or other disorders associated with chromosomal instability, provoke the expansion of aberrant clonotypes (Ig/TCR hybrids or TCR-γ/TCR-β hybrids; bottom) that are largely absent from the healthy. ALL, acute lymphoid leukaemia; GEM, germline-encoded, mycoyl-reactive; iNKT, invariant natural killer T; MAIT, mucosa-associated invariant T; MS, multiple sclerosis; pMHC, peptide-major histocompatibility complex; TCR, T cell receptor.

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