Replacement of TCR D? With Immunoglobulin DH DSP2.3 Imposes a Tyrosine-Enriched TCR Repertoire and Adversely Affects T Cell Development.

ABSTRACT: Enrichment for tyrosine in immunoglobulin CDR-H3 is due in large part to natural selection of germline immunoglobulin DH sequence. We have previously shown that when DH sequence is modified to reduce the contribution of tyrosine codons, epitope recognition is altered and B cell development, antibody production, autoantibody production, and morbidity and mortality following pathogen challenge are adversely affected. TCR? diversity (D?) gene segment sequences are even more highly conserved than DH, with trout D?1 identical to human and mouse D?1. We hypothesized that natural selection of D? sequence also shapes CDR-B3 diversity and influences T cell development and T cell function. To test this, we used a mouse strain that lacked D?2 and contained a novel D?1 allele (D?YTL) that replaces D?1 with an immunoglobulin DH, DSP2.3. Unlike D?1, wherein glycine predominates in all three reading frames (RFs), in DSP2.3 there is enrichment for tyrosine in RF1, threonine in RF2, and leucine in RF3. Mature T cells using D?YTL expressed TCRs enriched at particular CDR-B3 positions for tyrosine but depleted of leucine. Changing D? sequence altered thymocyte and peripheral T cell numbers and the T cell response to an ovalbumin immunodominant epitope. The differences in tyrosine content might explain, at least in part, why TCRs are more polyspecific and of lower affinity for their cognate antigens than their immunoglobulin counterparts.

SUBMITTER: Levinson M 

PROVIDER: S-EPMC7550431 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature