Intersection of population variation and autoimmunity genetics in human T cell activation
Author(s)
Ye, C. J.; Feng, T.; Kwon, H.-K.; Raj, T.; Wilson, M. T.; Asinovski, N.; McCabe, C.; Lee, M. H.; Frohlich, I.; Paik, H.-i.; Zaitlen, N.; Hacohen, N.; Stranger, B.; De Jager, P.; Mathis, D.; Benoist, C.; Regev, Aviv; ... Show more Show less
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T lymphocyte activation by antigen conditions adaptive immune responses and immunopathologies, but we know little about its variation in humans and its genetic or environmental roots. We analyzed gene expression in CD4[superscript +] T cells during unbiased activation or in T helper 17 (T[subscript H]17) conditions from 348 healthy participants representing European, Asian, and African ancestries. We observed interindividual variability, most marked for cytokine transcripts, with clear biases on the basis of ancestry, and following patterns more complex than simple T[subscript H]1/2/17 partitions. We identified 39 genetic loci specifically associated in cis with activated gene expression. We further fine-mapped and validated a single-base variant that modulates YY1 binding and the activity of an enhancer element controlling the autoimmune-associated IL2RA gene, affecting its activity in activated but not regulatory T cells. Thus, interindividual variability affects the fundamental immunologic process of T helper activation, with important connections to autoimmune disease.
Date issued
2014-09Department
Massachusetts Institute of Technology. Department of BiologyJournal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Ye, C. J. et al. “Intersection of Population Variation and Autoimmunity Genetics in Human T Cell Activation.” Science 345.6202 (2014): 1254665–1254665.
Version: Author's final manuscript
ISSN
0036-8075
1095-9203