Germline-Encoded TCR-MHC Contacts Promote TCR V Gene Bias in Umbilical Cord Blood T Cell Repertoire

Abstract

T cells recognize antigens as peptides bound to major histocompatibility complex (MHC) proteins through T cell receptors (TCRs) on their surface. To recognize a wide range of pathogens, each individual possesses a substantial number of TCRs with an extremely high degree of variability. It remains controversial whether germline-encoded TCR repertoire is shaped by MHC polymorphism and, if so, what is the preference between MHC genetic variants and TCR V gene compatibility. To investigate the “net” genetic association between MHC variations and TRBV genes, we applied quantitative trait locus (QTL) mapping to test the associations between MHC polymorphism and TCR β chain V (TRBV) genes usage using umbilical cord blood (UCB) samples of 201 Chinese newborns. We found TRBV gene and MHC loci that are predisposed to interact with one another differ from previous conclusions. The majority of MHC amino acid residues associated with the TRBV gene usage show spatial proximities in known structures of TCR-pMHC complexes. These results show for the first time that MHC variants bias TRBV gene usage in UCB of Chinese ancestry and indicate that germline-encoded contacts influence TCR-MHC interactions in intact T cell repertoires.

MHC-II alleles shape the CDR3 repertoires of conventional and regulatory naïve CD4+T cells

“…Such differences are likely to influence individual susceptibility to infections and autoimmunity and have implications for the future development of TCR-based diagnostics and therapies. (19)(20)(21). However, there is still a substantial gap in our understanding of how allelic variability in the MHC Class II locus shapes the intrinsic properties of naïve TCRα and TCRβ CDR3 repertoires.…”

Genetic and environmental determinants of human TCR repertoire diversity

“…MHC restriction is the cornerstone of T cell recognition [17], and prior reports have assessed the effect of the presence of specific MHC alleles on TCR V gene usage [18,19] and repertoire sharing [9,20]. These data, together with structural studies of the TCR-MHC interface [11,[21][22][23][24], have provided key insights into how the TCR binds MHC and peptide.…”

T cell Tolerance in Early Life

“…The shorter TCRs in neonatal T cells do not limit TCR diversity. The results from deep sequencing and single cell sequencing demonstrate higher diversity of TCR repertoire in human neonatal Tconv and Tregs when compared to adult ones ( 28 , 29 ). In addition, UCB Treg cells are also shown to have more clones with TCRs specific for autoantigens ( 28 ).…”