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

Abstract

Studies of individual T cells receptors (TCRs) have shed some light on structural features that underlie self-reactivity. However, general rules that predict whether TCRs are self-reactive have not been fully elucidated. Analyses of thymocytes expressing all Vβ family members show that the interfacial hydrophobicity of amino acids at positions 6 and 7 of the CDR3β segment robustly promotes the development of self-reactive TCRs. An index based on these findings distinguishes Vβ2+, Vβ6+ and Vβ8.2+ regulatory T cells from conventional T cells, as well as T cells selected on a major histocompatibility complex (MHC) allele associated with mouse type-1 diabetes from those selected on a non-autoimmune promoting MHC. These results provide a means for distinguishing normal and autoimmune-prone T cell repertoires.

Insights into immune system development and function from mouse T-cell repertoires

“…This lack of difference suggests that our measure of selection is mainly sensitive to basic selection against misfolding of the encoded receptor protein (which would have the same effect on thymic and blood repertoires) and is relatively insensitive to thymic selection against self-recognizing receptors (which would be present in blood but not in thymus). Negative selection in the thymus of course exists, but previous work on statistically characterizing its nature has shown that strong effects are localized in the few residues that actually contact presented peptides (33)(34)(35). Because we are statistically characterizing selection across the more extensive CDR3 region (11 aa long on average), it is perhaps not surprising that localized negative selection effects are washed out.…”

Low-affinity CD4+ T cells are major responders in the primary immune response

“…Nur77 expression has been used to readout functionality of CD4+ T cells in multiple systems29303132333435. Even though these T cells are functional, it does not describe the role these T cells are playing in the immune response.…”

Antigen-specific regulatory T-cell responses to intestinal microbiota

“…The different conclusion from the aforementioned TCR repertoire analyses 26 may relate to the different analytical approaches used to assess tTreg cell selection–intrathymic injection of TCR-expressing thymocytes 36 vs comparison with thymic TCR repertoires 26 . The conclusions may also be affected by the different TCRβ chains used 26, 36 or the use of a limited TCRα/fixed TCRβ model 26 , as effects on Treg cell selection has been reported for changes in a single TCR chain (TCRα 37 ). The ability of two of these colonic TCRs (CT2/CT6) to facilitate pTreg cell induction from naïve T cells in the periphery in normal mice was confirmed via the generation of transgenic (Tg) lines 33 .…”