title: Genetic variation in MHC proteins is associated with T cell receptor expression biases.
abstract: In 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 differences exist in TCR V gene compatibilities with different MHC alleles. We applied expression quantitative trait locus (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 identifies specific amino acids from MHC genes that bias V gene usage, many of which contact or are spatially proximal to the TCR or peptide in the TCR-peptide-MHC complex. 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-QTL effects mediated by protein-protein interactions and are consistent with intrinsic TCR-MHC specificity.
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.|Department of Biology, Stanford University, Stanford, California, USA.
authors.forename: Eilon
authors.identifier: 0000-0002-1262-350X
authors.initials: E
authors.lastname: Sharon
authors.affiliation: Department of Molecular Physiology, Stanford University School of Medicine, Stanford, California, USA.|Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA.|Immunology Program, Stanford University, Stanford, California, USA.
authors.forename: Leah V
authors.initials: LV
authors.lastname: Sibener
authors.affiliation: Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Alexis
authors.identifier: 0000-0002-5287-627X
authors.initials: A
authors.lastname: Battle
authors.affiliation: Department of Biology, Stanford University, Stanford, California, USA.
authors.forename: Hunter B
authors.initials: HB
authors.lastname: Fraser
authors.affiliation: Department of Molecular Physiology, Stanford University School of Medicine, Stanford, California, USA.|Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA.|Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
authors.affiliation: Department of Genetics, Stanford University, Stanford, California, USA.|Department of Biology, Stanford University, Stanford, California, USA.|Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Pritchard
mesh_terms: D015331:Cohort Studies; D014644:Genetic Variation / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism*; D008285:Major Histocompatibility Complex / Q000502:physiology*; D040641:Quantitative Trait Loci; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*
chemical_list: D007135:Immunoglobulin Variable Region; D011948:Receptors, Antigen, T-Cell