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Germline-encoded amino acids in the αβ T-cell receptor control thymic selection

Abstract

An αβ T-cell response depends on the recognition of antigen plus major histocompatibility complex (MHC) proteins1 by its antigen receptor (TCR). The ability of peripheral αβ T cells to recognize MHC is at least partly determined by MHC-dependent thymic selection, by which an immature T cell survives only if its TCR can recognize self MHC2,3,4,5,6,7. This process may allow MHC-reactive TCRs to be selected from a repertoire with completely random and unbiased specificities. However, analysis of thymocytes before positive selection indicated that TCR proteins might have a predetermined ability to bind MHC8,9,10,11. Here we show that specific germline-encoded amino acids in the TCR promote ‘generic’ MHC recognition and control thymic selection. In mice expressing single, rearranged TCR β-chains, individual mutation of amino acids in the complementarity-determining region (CDR) 2β to Ala reduced development of the entire TCR repertoire. Altogether, these results show that thymic selection is controlled by germline-encoded MHC contact points in the αβ TCR and indicate that the diversity of the peripheral T-cell repertoire is enhanced by this ‘built-in’ specificity.

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Figure 1: Vβ8.2 amino acids Y46, Y48 and E54 are required for TCR recognition of specific MHC–peptide and allo-MHC complexes.
Figure 2: Vβ8.2 amino acids Y46, Y48 and E54 promote efficient thymic selection.
Figure 3: Vβ6 Y46 promotes MHC recognition and thymic selection.
Figure 4: Altered TCRα repertoire in chimaeras expressing mutant TCR β-chains.

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Acknowledgements

We thank E. Huseby, K. Urdahl, C. Hsieh, G. Hernández-Hoyos and members of the Kappler/Marrack and Gapin laboratories for discussion. We thank the flow cytometry facilities at NJH and UCD for technical assistance with cell sorting and E. Kushnir for assistance with generating bone marrow chimaeras. We thank R. O’Brien and W. Born for providing Tcrb-/-Tcrd-/- mice and Y. Refaeli for providing stem cell cytokines. This work was supported by grants from the National Institutes of Health (AI18785 and AI22295 to P.M. and J.W.K. and AI057485 to L.G.). P.M. and J.W.K. are investigators of the Howard Hughes Medical Institute. J.P.S.-B. was supported by an NIH training grant (T32 AI07405).

Author Contributions J.P.S.-B., J.W.K., L.G. and P.M. designed research. J.P.S.-B., J.W., L.G. and P.M. performed experiments and analysed data. J.P.S.-B., L.G. and P.M. wrote the manuscript.

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Correspondence to James P. Scott-Browne or Philippa Marrack.

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Scott-Browne, J., White, J., Kappler, J. et al. Germline-encoded amino acids in the αβ T-cell receptor control thymic selection. Nature 458, 1043–1046 (2009). https://doi.org/10.1038/nature07812

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