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Hydrophobic CDR3 residues promote the development of self-reactive T cells

Nature Immunology volume 17, pages 946955 (2016) | Download Citation

Abstract

Studies of individual T cell antigen receptors (TCRs) have shed some light on structural features that underlie self-reactivity. However, the general rules that can be used to predict whether TCRs are self-reactive have not been fully elucidated. Here we found that the interfacial hydrophobicity of amino acids at positions 6 and 7 of the complementarity-determining region CDR3β robustly promoted the development of self-reactive TCRs. This property was found irrespective of the member of the β-chain variable region (Vβ) family present in the TCR or the length of the CDR3β. An index based on these findings distinguished Vβ2+, Vβ6+ and Vβ8.2+ regulatory T cells from conventional T cells and also distinguished CD4+ T cells selected by the major histocompatibility complex (MHC) class II molecule I-Ag7 (associated with the development of type 1 diabetes in NOD mice) from those selected by a non–autoimmunity-promoting MHC class II molecule I-Ab. Our results provide a means for distinguishing normal T cell repertoires versus autoimmunity-prone T cell repertoires.

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Acknowledgements

Supported by the US National Institutes of Health (RO1-DK095077 and U19 AI109858 to E.S.H., and T32 AI 007349 to B.D.S.), the University of Massachusetts Diabetes and Endocrine Research Center (DK32520 for E.S.H.), Marie Curie Research (I.G.T.), Fundacion Barrie (I.G.T.), the National Institute for Health Research Biomedical Research Centre based at Guy's and St Thomas' National Health Service Foundation Trust and King's College London (M.P.) and the Ragon Institute of MGH, MIT and Harvard (A.K.C.).

Author information

Affiliations

  1. Department of Pathology, University of Massachusetts Medical School Worcester, Massachusetts, USA.

    • Brian D Stadinski
    • , Jonathan Jung
    • , Katsuhiro Sasaki
    •  & Eric S Huseby
  2. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Karthik Shekhar
  3. Department of Immunobiology, King's College London, London, UK.

    • Iria Gómez-Touriño
    •  & Mark Peakman
  4. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.

    • Andrew K Sewell
  5. Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.

    • Arup K Chakraborty
  6. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Arup K Chakraborty
  7. Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Arup K Chakraborty
  8. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Arup K Chakraborty
  9. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Arup K Chakraborty
  10. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Arup K Chakraborty

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Contributions

B.D.S., K.S., A.K.S., M.P., A.K.C. and E.S.H. conceived of various aspects of the project and designed and interpreted experiments; B.D.S. performed TCR-sequencing experiments; B.D.S. and K.S. performed statistical analyses; B.D.S., K.S., I.G.-T., J.J., K.S. and E.S.H. performed experiments; and B.D.S., K.S., A.K.C. and E.S.H. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eric S Huseby.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8

Excel files

  1. 1.

    Supplementary Table 1

    Number of pMHC contacts created by CDR3β residues - atoms with 4Å distance

  2. 2.

    Supplementary Table 2

    PCR primers and bar codes for mouse and human TCR sequencing

  3. 3.

    Supplementary Table 3

    Genotype & Phenotype of murine T cells subsets and number of sorted T cells and Sequences analyzed

  4. 4.

    Supplementary Table 4

    Genotype of donors and number of sorted T cells

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DOI

https://doi.org/10.1038/ni.3491

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