A Direct Estimate of the Human αβ T Cell Receptor Diversity

Arstila, T. Petteri; Casrouge, Armanda; Baron, Véronique; Even, Jos; Kanellopoulos, Jean; Kourilsky, Philippe

doi:10.1126/science.286.5441.958

Cited by 840 publications

(675 citation statements)

References 30 publications

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“…The T cell repertoire exhibits a large diversity of its antigen receptors (TRCs); a human possesses approximately 10 7 − 10 8 TCRs (Arstila et al, 1999). This huge diversity of TCRs is generated by a random genetic recombination of the TCR encoding genes during the T cell maturation process (Krangel et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Stochastic competitive exclusion in the maintenance of the naïve T cell repertoire

Stirk

Lythe

Berg

et al. 2010

Journal of Theoretical Biology

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Recognition of antigens by the adaptive immune system relies on a highly diverse T cell receptor repertoire. The mechanism that maintains this diversity is based on competition for survival stimuli; these stimuli depend upon weak recognition of self-antigens by the T cell antigen receptor. We study the dynamics of diversity maintenance as a stochastic competition process between a pair of T cell clonotypes that are similar in terms of the self-antigens they recognise. We formulate a bivariate continuous-time Markov process for the numbers of T cells belonging to the two clonotypes. We prove that the ultimate fate of both clonotypes is extinction and provide a bound on mean extinction times. We focus on the case where the two clonotypes exhibit negligible competition with other T cell clonotypes in the repertoire, since this case provides an upper bound on the mean extinction times. As the two clonotypes become more similar in terms of the self-antigens they recognise, one clonotype quickly becomes extinct in a process resembling classical competitive exclusion. We study the limiting probability distribution for the bivariate process, conditioned on non-extinction of both clonotypes. Finally, we derive deterministic equations for the number of cells belonging to each clonotype as well as a linear Fokker-Planck equation for the fluctuations about the deterministic stable steady state.

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Section: Introductionmentioning

confidence: 99%

Stochastic competitive exclusion in the maintenance of the naïve T cell repertoire

Stirk

Lythe

Berg

et al. 2010

Journal of Theoretical Biology

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“…TCR are initially generated by V(D)J recombination, with specificities to a wide range of peptides, including self peptides generated from normal proteins produced by healthy cells [8,9]. Most self-reactive T cells are screened out early in their maturation process in the thymus, where they are exposed to a large array of the body's peptides presented on MHC molecules [10].…”

Section: Introductionmentioning

confidence: 99%

“…T cells detect the presence of pathogens when their receptors have sufficiently high affinity for the pMHC on a target cell and remain in contact with pMHC for a time sufficient to generate a stimulatory signal. Because the pMHC presents a single binding target for the TCR [7], both the peptide and the structure of the presenting MHC molecule play a role in determining affinity.TCR are initially generated by V(D)J recombination, with specificities to a wide range of peptides, including self peptides generated from normal proteins produced by healthy cells [8,9]. Most self-reactive T cells are screened out early in their maturation process in the thymus, where they are exposed to a large array of the body's peptides presented on MHC molecules [10].…”

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confidence: 99%

The effects of thymic selection on the range of T cell cross‐reactivity

Chao¹,

Davenport²,

Forrest³

et al. 2005

Eur J Immunol

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Based on the results of a computational model of thymic selection, we propose a mechanism that produces the observed wide range of T cell cross-reactivity. The model suggests that the cross-reactivity of a T cell that survives thymic selection is correlated with its affinity for self peptides. In order to survive thymic selection, a T cell with low affinity for all self peptides expressed in the thymus must have high affinity for major histocompatibility complex (MHC), which makes it highly cross-reactive. A T cell with high affinity for any self peptide must have low MHC affinity to survive selection, which makes it highly specific for its cognate peptide. Our model predicts that (1) positive selection reduces by only 17% the number of T cells that can detect any given foreign peptide, even though it eliminates over 95% of pre-selection cells; (2) negative selection decreases the average cross-reactivity of the pre-selection repertoire by fivefold; and (3) T cells responding to foreign peptides similar to self peptides will have a lower average cross-reactivity than cells responding to epitopes dissimilar to self. IntroductionThe ability of an individual T cell to recognize related antigenic peptides is an essential part of the body's defense against mutating pathogens. T cells detect intracellular pathogens by binding to foreign peptides presented by major histocompatibility complex (MHC)-encoded proteins on the surfaces of infected cells or on specialized antigen-presenting cells [1][2][3]. Although T cells are specific to their cognate peptides, they crossreact with many others [4]. It has been estimated that a T cell can detect an average of 10 6 different peptides [5]. However, not all T cells are equally cross-reactive; it has been observed that the number of peptides to which a single T cell can respond varies widely [6].T cell recognition of antigen is determined by binding interactions of T cell receptors (TCR) with peptide-MHC complexes (pMHC). Each T cell expresses thousands of copies of identical TCR that bind with high affinity to their cognate peptide presented by MHC. T cells detect the presence of pathogens when their receptors have sufficiently high affinity for the pMHC on a target cell and remain in contact with pMHC for a time sufficient to generate a stimulatory signal. Because the pMHC presents a single binding target for the TCR [7], both the peptide and the structure of the presenting MHC molecule play a role in determining affinity.TCR are initially generated by V(D)J recombination, with specificities to a wide range of peptides, including self peptides generated from normal proteins produced by healthy cells [8,9]. Most self-reactive T cells are screened out early in their maturation process in the thymus, where they are exposed to a large array of the body's peptides presented on MHC molecules [10]. During positive selection, T cells that have an extremely low avidity to self peptides bound to MHC die by neglect [11][12][13]. It is believed that this process eliminates T cells that ha...

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“…The TCR is generated by gene segment rearrangements in which nucleotides can be removed or added randomly at the junctions between the segments, generating as much as 2.5 ϫ 10 7 to 1 ϫ 10 8 different TCRs (23). Most variability can be found in the third complementaritydetermining region (CDR3).…”

mentioning

confidence: 99%

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

Cantaert¹,

Brouard²,

Thurlings³

et al. 2009

Arthritis & Rheumatism

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Objective. The association of HLA-DRB1 alleles with anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) suggests the potential involvement of T lymphocytes in ACPA-seropositive disease. The purpose of this study was to investigate this hypothesis by systematic histologic and molecular analyses of synovial T cells in ACPA؉ versus ACPA-RA patients.Methods. Synovial biopsy samples were obtained from 158 RA patients. Inflammation was determined histologically and immunohistochemically. RNA was extracted from peripheral blood mononuclear cells and synovial tissues obtained from 11 ACPA؉ RA patients, 7 ACPA-RA patients, and 10 spondylarthritis (SpA) patients (arthritis controls). T lymphocyte clonality was studied by combined quantitative and qualitative T cell receptor CDR3 length distribution (LD) analysis and direct sequencing analysis.Results. ACPA؉ and ACPA-RA patients were similar at both the clinical and histologic levels. At the molecular level, however, patients with ACPA؉ synovitis displayed a marked elevation of qualitative CDR3 LD alterations as compared with those with ACPA-synovitis and with the SpA controls. These differences in CDR3 LD were not observed in the peripheral blood, indicating a selective recruitment and/or local expansion of T cells in the synovial compartment. The CDR3 LD alterations reflected true monoclonal or oligoclonal expansions, as confirmed by direct sequencing of the T cell receptor. The CDR3 LD alterations in RA synovium did not correlate with B cell clonal expansions but were inversely associated with synovial lymphoid neogenesis.Conclusion. The T cell repertoire is specifically restricted in RA patients with ACPA؉ synovitis. Whereas the origin and role of these clonal alterations remain to be determined, our data suggest the preferential involvement of T lymphocytes in ACPAseropositive RA.

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A Direct Estimate of the Human αβ T Cell Receptor Diversity

Cited by 840 publications

References 30 publications

Stochastic competitive exclusion in the maintenance of the naïve T cell repertoire

Stochastic competitive exclusion in the maintenance of the naïve T cell repertoire

The effects of thymic selection on the range of T cell cross‐reactivity

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

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