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The molecular basis of TCR germline bias for MHC is surprisingly simple

Abstract

The elusive etiology of germline bias of the T cell receptor (TCR) for major histocompatibility complex (MHC) has been clarified by recent 'proof-of-concept' structural results demonstrating the conservation of specific TCR-MHC interfacial contacts in complexes bearing common variable segments and MHC allotypes. We suggest that each TCR variable-region gene product engages each type of MHC through a 'menu' of structurally coded recognition motifs that have arisen through coevolution. The requirement for MHC-restricted T cell recognition during thymic selection and peripheral surveillance has necessitated the existence of such a coded recognition system. Given these findings, a reconsideration of the TCR–peptide-MHC structural database shows that not only have the answers been there all along but also they were predictable by the first principles of physical chemistry.

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Figure 1: Divergence and convergence of TCR footprints on MHC molecules.
Figure 2: The 'codon hypothesis' for germline TCR-MHC interactions.

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Acknowledgements

We thank J. Kuriyan and D. Kranz for discussions. Supported by the National Health and Medical Research Council (CJ Martin Fellowship to L.K.E.), the Canadian Institute of Health Research (J.J.A.), N.I.H. (D.F., K.C.G.) and the Howard Hughes Medical Institute (K.C.G.).

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Christopher Garcia, K., Adams, J., Feng, D. et al. The molecular basis of TCR germline bias for MHC is surprisingly simple. Nat Immunol 10, 143–147 (2009). https://doi.org/10.1038/ni.f.219

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