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

Brian D. Stadinski; Karthik Shekhar; Iria Gómez-Touriño; Jonathan Jung; Katsuhiro Sasaki; Andrew K. Sewell; Mark Peakman; Arup K. Chakraborty; Eric S. Huseby

doi:10.1038/ni.3491

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

Brian D. Stadinski, Karthik Shekhar, Iria Gómez-Touriño, Jonathan Jung, Katsuhiro Sasaki, Andrew K. Sewell, Mark Peakman, Arup K. Chakraborty, Eric S. Huseby

Research output: Contribution to journal › Article › peer-review

120 Scopus citations

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 (V β) family present in the TCR or the length of the CDR3β. An index based on these findings distinguished V β 2⁺, V β 6⁺ and V β 8.2⁺ regulatory T cells from conventional T cells and also distinguished CD4⁺ T cells selected by the major histocompatibility complex (MHC) class II molecule I-A g7 (associated with the development of type 1 diabetes in NOD mice) from those selected by a non-autoimmunity-promoting MHC class II molecule I-A b. Our results provide a means for distinguishing normal T cell repertoires versus autoimmunity-prone T cell repertoires.

Original language	English
Pages (from-to)	946-955
Number of pages	10
Journal	Nature Immunology
Volume	17
Issue number	8
DOIs	https://doi.org/10.1038/ni.3491
State	Published - Aug 2016
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016 Nature America, Inc.

Funding

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.).

Funders	Funder number
A.K.C.
Fundacion Barrie
Guy's and St Thomas' National Health Service Foundation Trust
Marie Curie Research
Ragon Institute of MGH
University of Massachusetts Diabetes and Endocrine Research Center	DK32520
National Institutes of Health	T32 AI 007349, RO1-DK095077
National Institute of Allergy and Infectious Diseases	U19AI109858
Massachusetts Institute of Technology
Harvard University
King's College London
National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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 (V β) family present in the TCR or the length of the CDR3β. An index based on these findings distinguished V β 2+, V β 6+ and V β 8.2+ regulatory T cells from conventional T cells and also distinguished CD4+ T cells selected by the major histocompatibility complex (MHC) class II molecule I-A g7 (associated with the development of type 1 diabetes in NOD mice) from those selected by a non-autoimmunity-promoting MHC class II molecule I-A b. Our results provide a means for distinguishing normal T cell repertoires versus autoimmunity-prone T cell repertoires.",

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

Abstract

Bibliographical note

Funding

UN SDGs

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