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

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-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.

• Authors: Brian D Stadinski, Karthik Shekhar, Iria Gómez-Touriño, Jonathan Jung, Katsuhiro Sasaki, Andrew K Sewell, Mark Peakman, Arup K Chakraborty, Eric S Huseby
• Journal: Nature immunology (Nat Immunol) Vol. 17 Issue 8 Pg. 946-55 (08 2016) ISSN: 1529-2916 [Electronic] United States
• PMID: 27348411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• Animals
• Autoantigens (immunology, 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)