Genetic variation in MHC proteins is associated with T cell receptor expression biases

Abstract

Within each individual, a highly diverse T cell receptor (TCR) repertoire interacts with peptides presented by major histocompatibility complex (MHC) molecules. Despite extensive research, it remains controversial whether germline-encoded TCR-MHC contacts promote TCR-MHC specificity and if so, whether there exist differences in TCR V-gene compatibilities with different MHC alleles. We applied eQTL mapping to test for associations between genetic variation and TCR V-gene usage in a large human cohort. We report strong trans associations between variation in the MHC locus and TCR V-gene usage. Fine mapping of the association signals reveals specific amino acids in MHC genes that bias V-gene usage, many of which contact or are spatially proximal to the TCR or peptide. Hence, these MHC variants, several of which are linked to autoimmune diseases, can directly affect TCR-MHC interaction. These results provide the first examples of trans-QTLs mediated by protein-protein interactions, and are consistent with intrinsic TCR-MHC specificity.

A TCRα framework–centered codon shapes a biased T cell repertoire through direct MHC and CDR3β interactions

“…In general, the molecular basis for selection of biased TCR repertoires is not well understood, but has been suggested to involve a combination of preferences in the somatic rearrangement machinery (2) and germline-encoded features that influence thymic selection (3). A recent study showed a strong trans association between variation in the MHC locus and TCR variable (V) gene usage, further suggesting a codependent expression pattern (4). However, it is still unclear if and how certain TCR V genes are predisposed to interact with MHC and underlie the existence of biased repertoires.…”

MHC Bias by T Cell Receptors: Genetic Evidence for MHC and TCR Coevolution

“…The fact this does not happen leads to an intrinsic bias between TCRs and A*0201 by definition. Similar features of evolved compatibility, with ranges of compatibility and strengths of interatomic “glue” likely exist elsewhere between TCR and MHC proteins, contributing to the genetic linkage detected by Sharon et al [10]. …”

“…The recent studies of Sharon et al . published in Nature Genetics provide evidence for this link [10]. Using expression quantitative trait loci (eQTL) analysis, the authors show linkage between multiple MHC and TCR genes.…”

Structural and Mechanistic Implications of Rearrangement Frequencies within Human TCRBV Genes

“…There has been a long held theory of a co-evolution of MHC and TCR (26–28), which has interested us as well (29). Analysis of this co-evolution is predominantly based on CDR1 and CDR2 contributions as these are the major germ-line components that define the V region, and on which selection and thus evolution can function.…”