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

Nature Chemical Biologyvolume 14pages934942 (2018) | Download Citation


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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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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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.

Author information


  1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA

    • Timothy P. Riley
    • , Lance M. Hellman
    •  & Brian M. Baker
  2. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, USA

    • Timothy P. Riley
    • , Lance M. Hellman
    •  & Brian M. Baker
  3. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA

    • Marvin H. Gee
    • , Juan L. Mendoza
    • , Jesus A. Alonso
    •  & K. Christopher Garcia
  4. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA

    • Marvin H. Gee
    • , Juan L. Mendoza
    • , Jesus A. Alonso
    •  & K. Christopher Garcia
  5. Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL, USA

    • Kendra C. Foley
    •  & Michael I. Nishimura
  6. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA

    • Craig W. Vander Kooi


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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.

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.

Corresponding author

Correspondence to Brian M. Baker.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Tables 1–4, Supplementary Figures 1–4

  2. Reporting Summary

  3. Supplementary Video 1

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

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