Intersection of population variation and autoimmunity genetics in human T cell activation

Chun Jimmie Ye, Ting Feng, Ho Keun Kwon, Towfique Raj, Michael T. Wilson, Natasha Asinovski, Cristin McCabe, Michelle H. Lee, Irene Frohlich, Hyun Il Paik, Noah Zaitlen, Nir Hacohen, Barbara Elaine Stranger, Philip De Jager, Diane Mathis, Aviv Regev*, Christophe Benoist

*Corresponding author for this work

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

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+T cells during unbiased activation or in T helper 17 (TH17) 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 TH1/2/17 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.

Original languageEnglish (US)
Article number1254665
JournalScience
Volume345
Issue number6202
DOIs
StatePublished - Sep 12 2014

ASJC Scopus subject areas

  • General

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    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. E., De Jager, P., Mathis, D., Regev, A., & Benoist, C. (2014). Intersection of population variation and autoimmunity genetics in human T cell activation. Science, 345(6202), [1254665]. https://doi.org/10.1126/science.1254665