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

Jonathan Pritchard, Christopher Garcia and colleagues examine associations between different T cell receptor V genes and MHC alleles by eQTL mapping. They find that there are strong associations between MHC variation and T cell receptor gene usage and map these signals to specific MHC amino acids, m...

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Vydáno v:	Nature genetics Ročník 48; číslo 9; s. 995 - 1002
Hlavní autoři:	Sharon, Eilon, Sibener, Leah V, Battle, Alexis, Fraser, Hunter B, Garcia, K Christopher, Pritchard, Jonathan K
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.09.2016 Nature Publishing Group
Témata:	38/39 38/43 45/91 631/208/199 631/208/205/2138 631/208/248 631/250/248 Agriculture Amino acids Analysis Animal Genetics and Genomics Bias Biomedicine Cancer Research Cohort Studies Gene expression Gene Function Gene mapping Genes Genetic diversity Genetic variation Genetic Variation - genetics Genomes Genotype & phenotype Health aspects High-Throughput Nucleotide Sequencing Human Genetics Humans Identification and classification Immunoglobulin Variable Region - genetics Immunoglobulin Variable Region - metabolism Lymphocytes Major Histocompatibility Complex - physiology Membrane proteins Peptides Properties Proteins Quantitative Trait Loci Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - metabolism Scholarships & fellowships T cell receptors
ISSN:	1061-4036, 1546-1718, 1546-1718
On-line přístup:	Získat plný text
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Shrnutí:	Jonathan Pritchard, Christopher Garcia and colleagues examine associations between different T cell receptor V genes and MHC alleles by eQTL mapping. They find that there are strong associations between MHC variation and T cell receptor gene usage and map these signals to specific MHC amino acids, many of which physically interact with germline-encoded amino acids on the T cell receptor. 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.
Bibliografie:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/ng.3625