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

Nat Immunol. 2016 Aug;17(8):946-55. doi: 10.1038/ni.3491. Epub 2016 Jun 27.


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-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoantigens / immunology
  • Autoantigens / metabolism
  • Autoimmunity*
  • Cell Differentiation
  • Central Tolerance
  • Complementarity Determining Regions / genetics*
  • Diabetes Mellitus, Type 1 / immunology*
  • Female
  • High-Throughput Nucleotide Sequencing
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • T-Lymphocyte Subsets / physiology*
  • T-Lymphocytes, Regulatory / physiology*


  • Autoantigens
  • Complementarity Determining Regions
  • Histocompatibility Antigens Class II
  • I-A g7 antigen
  • I-A(b) antigen, mouse