Germ Line-governed Recognition of a Cancer Epitope by an Immunodominant Human T-cell Receptor

Cole, David K.; Yuan, Fang; Rizkallah, P.J.; Miles, John J.; Gostick, Emma; Price, David A.; Gao, George F.; Jakobsen, Bent K.; Sewell, Andrew K.

doi:10.1074/jbc.m109.022509

Cited by 136 publications

(226 citation statements)

References 47 publications

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“…What are the parameters that could contribute to the observed hierarchy of Ag-specific T-cell frequencies, and to the correlation between such a hierarchy and thymic selection efficiency? Firstly, MelA-and PGT-A2-specific T-cell repertoires are strongly biased toward expression of TRAV12-2 + TCRs, and the structural analyses of the MelA-A2-TCR ternary complexes available so far [21,22] indicate a major contribution of germline (CDR1 and CDR2) loops from this particular TRAV gene to TCR/p-MHC interaction. Therefore, the high frequency of T cells specific for these p-MHC observed in the various thymic compartments may originate from a structural predisposition of the TRAV12-2 TCR segment to interact with MelA-A2 and PGT-A2.…”

Section: Discussionmentioning

confidence: 99%

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

et al. 2015

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In the thymus, a T-cell repertoire able to confer protection against infectious and noninfectious agents in a peptide-dependent, self-MHC-restricted manner is selected. Direct detection of Ag-specific thymocytes, and analysis of the impact of the expression of the MHCrestricting allele on their frequency or function has never been studied in humans because of the extremely low precursor frequency. Here, we used a tetramer-based enrichment protocol to analyze the ex vivo frequency and activation-phenotype of human thymocytes specific for self, viral and tumor-antigens presented by HLA-A*0201 (A2) in individuals expressing or not this allele. Ag-specific thymocytes were quantified within both CD4CD8 double or single-positive compartments in every donor. Our data indicate that the maturation efficiency of Ag-specific thymocytes is poorly affected by HLA-A2 expression, in terms of frequencies. Nevertheless, A2-restricted T-cell lines from A2 + donors reacted to A2 + cell lines in a highly peptide-specific fashion, whereas their alloreactive counterparts showed off-target activity. This first ex vivo analysis of human antigen-specific thymocytes at different stages of human T-cell development should open new perspectives in the understanding of the human thymic selection process. Keywords: Antigen r Human T cells r MHC r Tetramers r Thymocytes See accompanying Commentary by Ciucci and BosselutAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe thymus generates a highly diverse T-cell repertoire able to recognize virtually any antigen that could be encountered by a given individual along his/her life. This diversity is achieved through two main mechanisms. First by the acquisition by CD4 + CD8 + double-positive (DP) thymocytes of a clonally distributed T cell receptor (TCR) that is generated after somatic recombination of TCR V(D)J gene segments and nontemplated nucleotide Correspondence: Dr. Xavier Saulquin e-mail: xavier.saulquin@univ-nantes.fradditions. This quasi-random mechanism allows for the generation of up to 10 15 different receptors [1]. Second, by the shaping of this initial T-cell repertoire by positive and negative thymic selection processes that will favor emergence of a self major histocompatibility molecules (MHC)-restricted, yet self-tolerant, TCR repertoire carried by mature naïve single-positive (SP) T cells. As a consequence of this maturation process, the diversity of SP αβ T cells in a given individual falls in the range of 10 6 to 10 8 [2]. * LH and FL equally contributed to this work. The respective contributions of positive and negative thymic selection processes to the generation of a mature T-cell repertoire possibly biased towards recognition of peptides restricted by host MHC alleles are still debated. Indeed, this phenomenon referred to as "host or Self-MHC-restriction" is a consequence of a balance between (i) the need for a thymocyte to get survival signals from TCR upon interactions of weak/intermediate avidi...

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Section: Discussionmentioning

confidence: 99%

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

et al. 2015

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“…The HLA A p 0201-restricted Melan-A/MART-1 [26][27][28][29][30][31][32][33][34][35] ELAGIGILTV-specific MEL5 clone and the HLA A p 0201-restricted preproinsulin [15][16][17][18][19][20][21][22][23][24] ALWGPDPAAAspecific 1E6 clone were described previously (22)(23)(24). PBMCs from an HLA A p 0201 + donor were primed with either ELAGIGILTVor EAAGIGILTV as described previously (25).…”

Section: Generation Of Cd8mentioning

confidence: 99%

“…For the recognition screen, 2 3 10 3 1E6 CD8 + T cells were cultured in triplicate for 16 h with position 2 (p2) variants of the wild type preproinsulin [15][16][17][18][19][20][21][22][23][24] peptide (ALWGPDPAAA) at a concentration of 1 mg/ml. Supernatant was harvested and analyzed for TNF-a production by ELISA according to the manufacturer's instructions (Life Technologies, Paisley, U.K. + T cells were washed and rested overnight in RPMI 1640 containing 100 U/ml penicillin, 100 mg/ml streptomycin, 2 mM L-glutamine, and 2% heatinactivated FCS (R2 medium; Life Technologies).…”

Section: Recognition Screen and Combinatorial Peptide Library Scanmentioning

confidence: 99%

Modification of MHC Anchor Residues Generates Heteroclitic Peptides That Alter TCR Binding and T Cell Recognition

Cole

Edwards

Wynn

et al. 2010

The Journal of Immunology

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167

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Improving T-cell antigens by altering MHC anchor residues is a common strategy used to enhance peptide vaccines but there has been little assessment of how such modifications affect TCR binding and T-cell recognition. Here, we use surface plasmon resonance and peptide-MHC tetramer binding at the cell surface to demonstrate that changes in primary peptide anchor residues can substantially and unpredictably alter TCR binding. We also demonstrate that the ability of TCRs to differentiate between natural and anchor-modified heteroclitic peptides distinguishes T-cells that exhibit a strong preference for either type of antigen. Furthermore, we show that anchor-modified heteroclitic peptides prime T-cells with different TCRs compared to those primed with natural antigen. Thus, vaccination with heteroclitic peptides may elicit T-cells that exhibit suboptimal recognition of the intended natural antigen and, consequently, impaired functional attributes in vivo. Heteroclitic peptide-based immune interventions therefore require careful evaluation to ensure efficacy in the clinic.

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“…Other studies have established that biased TCR use may also reflect the selection of TCRs with optimal structural characteristics that impart exquisite specificity for a given pMHC molecular topography (18)(19)(20)(21)(22)(23)(24)(25). Such antigen-driven selection will, of course, be shaped by other factors, such as the availability of naive T-cell precursors and the level and duration of antigenpresentation during infection.…”

mentioning

confidence: 99%

Structural basis for enabling T-cell receptor diversity within biased virus-specific CD8 ⁺ T-cell responses

Day¹,

Guillonneau²,

Gras

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Pathogen-specific responses are characterized by preferred profiles of peptide+class I MHC (pMHCI) glycoprotein-specific T-cell receptor (TCR) Variable (V)-region use. How TCRV-region bias impacts TCRαβ heterodimer selection and resultant diversity is unclear. The D b PA 224 -specific TCR repertoire in influenza A virusinfected C57BL/6J (B6) mice exhibits a preferred TCRV-region bias toward the TRBV29 gene segment and an optimal complementarity determining region (CDR3) β-length of 6 aa. Despite these restrictions, D b PA 224 -specific BV29 + T cells use a wide array of unique CDR3β sequences. Structural characterization of a single, TRBV29 + D b P A224 -specific TCRαβ-pMHCI complex demonstrated that CDR3α amino acid side chains made specific peptide interactions, but the CDR3β main chain exclusively contacted peptides. Thus, length but not amino acid sequence was key for recognition and flexibility in Vβ-region use. In support of this hypothesis, retrovirus expression of the D b PA 224 -specific TCRVα-chain was used to constrain pairing within a naive/immune epitope-specific repertoire. The retrogenic TCRVα paired with a diversity of CDR3βs in the context of a preferred TCRVβ spectrum. Overall, these data provide an explanation for the combination of TCRV region bias and diversity within selected repertoires, even as they maintain exquisite pMHCI specificity.T cell repertoire | T-cell receptor bias | crystal structure T he adaptive T-cell response to viruses is mediated via T-cell receptor (TCR)-αβ glycoprotein heterodimer recognition of pathogen-derived peptides (p) complexed to cell-surface MHC glycoproteins. During T-cell development, somatic recombination of variable (V) and joining (J) or V, diversity (D), and J gene segments (1) leads to the emergence of a diverse spectrum of TCRα-and TCRβ-chains. Segments of hypervariability within the Vα and Vβ domains, termed complementarity determining regions (CDRs), form the TCRαβ binding site and mediate contact with a given pMHC complex. Although the CDR1 and -2 regions are determined by germ-line sequences of V-genes, the CDR3 region is encoded at the junction of spliced VJ (TCRα) and VDJ (TCRβ) gene segments. The murine TCRβ (TRB) locus consists of 35 V, 2 D, and 12 J gene segments and the TCRα (TRA) locus has 71 V and 60 J gene segments (2). Beyond the random splicing of different TCRα and TCRβ genes, the overall spectrum of TCR diversity largely reflects the inefficient splicing of DNA encoding the CDR3α and CDR3β loops (3) plus the addition of nontemplated encoded nucleotides at the V(D)J junctions (4). Finally, different pairings of rearranged TCRα-and TCRβ-chains are selected during thymic differentiation to give the naive TCRαβ repertoire.

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Germ Line-governed Recognition of a Cancer Epitope by an Immunodominant Human T-cell Receptor

Cited by 136 publications

References 47 publications

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

Modification of MHC Anchor Residues Generates Heteroclitic Peptides That Alter TCR Binding and T Cell Recognition

Structural basis for enabling T-cell receptor diversity within biased virus-specific CD8 ⁺ T-cell responses

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Germ Line-governed Recognition of a Cancer Epitope by an Immunodominant Human T-cell Receptor

Cited by 136 publications

References 47 publications

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

Modification of MHC Anchor Residues Generates Heteroclitic Peptides That Alter TCR Binding and T Cell Recognition

Structural basis for enabling T-cell receptor diversity within biased virus-specific CD8 + T-cell responses

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Structural basis for enabling T-cell receptor diversity within biased virus-specific CD8 ⁺ T-cell responses