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

Science
Authors
Keywords
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 (T(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(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.

Year of Publication
2014
Journal
Science
Volume
345
Issue
6202
Pages
1254665
Date Published
2014 Sep 12
ISSN
1095-9203
URL
DOI
10.1126/science.1254665
PubMed ID
25214635
PubMed Central ID
PMC4751028
Links
Grant list
F32 AG043267 / AG / NIA NIH HHS / United States
RC2 GM093080 / GM / NIGMS NIH HHS / United States
Howard Hughes Medical Institute / United States