T cell receptor cross-reactivity expanded by dramatic peptide–MHC adaptability

Abstract

T cell receptor cross-reactivity allows a fixed T cell repertoire to respond to a much larger universe of potential antigens. Recent work has emphasized the importance of peptide structural and chemical homology, as opposed to sequence similarity, in T cell receptor cross-reactivity. Surprisingly, though, T cell receptors can also cross-react between ligands with little physiochemical commonalities. Studying the clinically relevant receptor DMF5, we demonstrate that cross-recognition of such divergent antigens can occur through mechanisms that involve heretofore unanticipated rearrangements in the peptide and presenting MHC protein, including binding-induced peptide register shifts and extensions from MHC peptide binding grooves. Moreover, cross-reactivity can proceed even when such dramatic rearrangements do not translate into structural or chemical molecular mimicry. Beyond demonstrating new principles of T cell receptor cross-reactivity, our results have implications for efforts to predict and control T cell specificity and cross-reactivity and highlight challenges associated with predicting T cell reactivities.

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Fig. 1: Two distinctive classes of peptides recognized by the DMF5 TCR.
Fig. 2: The DRG peptide MMWDRGLGMM adopts a conformation distinct from that of MART-1 when bound to HLA-A2 and perturbs the structure of the HLA-A2 α2 helix.
Fig. 3: The DMF5 TCR does not show a preference for DRG vs. GIG peptides but the classes are recognized via distinct mechanisms.
Fig. 4: DMF5 recognizes the GIG peptides with common structural solutions.
Fig. 5: DMF5 recognizes the MMWDRGLGMM DRG peptide very differently, inducing a peptide register shift and C-terminal extension while returning the HLA-A2 α2 helix to its usual conformation.
Fig. 6: The GIG and register-shifted DRG surfaces are recognized by DMF5 through small TCR side chain rearrangements and differential use of interfacial water.

Data availability

Crystallographic data sets are available in the PDB repository under ascension codes 6AMT (MMWDRGLGMM/HLA-A2), 6AMU (DMF5-MMWDRGLGMM/HLA-A2), and 6AM5 (DMF5-SMLGIGIVPV/HLA-A2). Other data are available from the corresponding author upon request.

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Acknowledgements

Authors were supported by NIH grants GM118166 and AI29543 (B.M.B.); CA154778 and CA153789 (M.I.N.); and AI103867 (K.C.G.); and American Cancer Society grant IRG-14-195-01 (L.M.H.). T.P.R. and J.A.A. were supported by fellowships from the Indiana CTSI, funded in part by NIH grants TR001107 and TR001108. M.H.G. was supported by a Stanford Graduate Research Fellowship and NIH grant CA216926. J.L.M. was supported by NIH grant CA175127. K.C.G. is supported by the Howard Hughes Medical Institute and the Parker Institute for Cancer Immunotherapy.

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Contributions

Modeling, crystallographic, and TCR binding experiments were performed by T.P.R., L.M.H., and J.A.A. C.W.V.K assisted with crystallographic data collection and analysis. Thermal stability experiments were performed by T.P.R. and L.M.H. Functional experiments were performed by L.M.H. with assistance from K.C.F. in T cell transduction. Data analysis was performed by T.P.R., L.M.H., M.H.G., J.L.M., J.A.A., and C.W.V.K. The manuscript was drafted and edited by T.P.R., M.H.G., J.L.M., and B.M.B. The project was conceptualized by T.P.R., K.C.G., and B.M.B. Personnel were supervised by M.I.N., K.C.G., and B.M.B.

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Correspondence to Brian M. Baker.

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Competing interests

T.P.R. is employed by a new startup company that uses structural information to explore and modulate TCR specificity. B.M.B. is on the board of this company.

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Supplementary Text and Figures

Supplementary Tables 1–4, Supplementary Figures 1–4

Reporting Summary

Supplementary Video 1

Animation shown the transition of the MMWDRGLGMM/HLA-A2 complex from TCR-free to TCR-bound

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Riley, T.P., Hellman, L.M., Gee, M.H. et al. T cell receptor cross-reactivity expanded by dramatic peptide–MHC adaptability. Nat Chem Biol 14, 934–942 (2018). https://doi.org/10.1038/s41589-018-0130-4

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