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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.

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Figure 1: Illustration of our approach.
Figure 2: Expression of TCR Vα and Vβ genes is significantly associated with genetic variation in the MHC locus.
Figure 3: Expression of TCR Vα and Vβ genes is associated with amino acid variation in MHC proteins.
Figure 4: Bayesian inference of amino acid residues encoded in MHC genes that influence expression of TCR Vα genes.
Figure 5: MHC residues that are functionally important for TCR recognition are also associated with TCR expression.

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Acknowledgements

We thank D. Golan, D. Knowles, A. Fu, M. Birnbaum, M. Gee, J. Mendoza, A. Bhaskar and T. Raj for helpful discussions and the anonymous referees for valuable comments. This work was supported by NIH grants HG0070736, 1R01GM097171-01A1, RO1AI03867 and U19AI057229, the Howard Hughes Medical Institute, the EMBO Long-Term Fellowship and a National Science Foundation Graduate Research Fellowship.

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Authors and Affiliations

Authors

Contributions

E.S., J.K.P. and K.C.G. conceived the project. E.S. performed genetic analyses with input from A.B., H.B.F. and J.K.P. E.S. and L.V.S. performed structural analyses with input from K.C.G. E.S., L.V.S., K.C.G. and J.K.P. wrote the manuscript. The work was supervised by K.C.G. and J.K.P. All authors reviewed, revised and provided feedback on the manuscript.

Corresponding authors

Correspondence to K Christopher Garcia or Jonathan K Pritchard.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–32 and Supplementary Table 1 (PDF 17162 kb)

Supplementary Table 2

TCR V genes expression. (XLSX 930 kb)

Supplementary Table 3

Ig V-genes expression. (XLSX 1070 kb)

Supplementary Table 4

TCR and Ig V genes association with short-range genetic variation and genetic variation in the MHC locus. (XLSX 88 kb)

Supplementary Table 5

Most significance association between expression of each TCR and Ig V gene and genotyped SNPs in the MHC locus. (XLSX 76 kb)

Supplementary Table 6

Nucleotide and amino acid variants in the MHC locus that are independently associated with single TCR Vα or Vβ gene expression. (XLSX 70 kb)

Supplementary Table 7

Expression variation of TCR Vα and Vβ genes explained by indepedent associations with SNP and amino acid variation in the MHC locus. (XLSX 54 kb)

Supplementary Table 8

Expression variation of TCR Vα and Vβ genes explained by indepedent associations with four-digit haplotypes for classical MHC genes. (XLSX 12 kb)

Supplementary Table 9

Probabilities that classical MHC gene amino acid positions influences expression of any TCR Vα gene. (XLSX 62 kb)

Supplementary Table 10

Probabilities that classical MHC gene amino acid positions influences expression of any TCR Vβ gene. (XLSX 61 kb)

Supplementary Table 11

A list of PDB accession codes, MHC alleles and TCR Vα gene used in the analysis of TCR–pMHC complexes. (XLSX 58 kb)

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Sharon, E., Sibener, L., Battle, A. et al. Genetic variation in MHC proteins is associated with T cell receptor expression biases. Nat Genet 48, 995–1002 (2016). https://doi.org/10.1038/ng.3625

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