Publication Date:
2014-09-13
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751028/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751028/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ye, Chun Jimmie -- Feng, Ting -- Kwon, Ho-Keun -- Raj, Towfique -- Wilson, Michael T -- Asinovski, Natasha -- McCabe, Cristin -- Lee, Michelle H -- Frohlich, Irene -- Paik, Hyun-il -- Zaitlen, Noah -- Hacohen, Nir -- Stranger, Barbara -- De Jager, Philip -- Mathis, Diane -- Regev, Aviv -- Benoist, Christophe -- F32 AG043267/AG/NIA NIH HHS/ -- RC2 GM093080/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Sep 12;345(6202):1254665. doi: 10.1126/science.1254665.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. ; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. ; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, MA 02115, USA. ; Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, MA 02115, USA. ; Department of Medicine Lung Biology Center, University of California, San Francisco, San Francisco, CA 94158, USA. ; Section of Genetic Medicine, University of Chicago, Chicago, IL 60637, USA. ; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. ; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. aregev@broad.mit.edu cbdm@hms.harvard.edu. ; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA. aregev@broad.mit.edu cbdm@hms.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25214635" target="_blank"〉PubMed〈/a〉
Keywords:
African Continental Ancestry Group/genetics
;
Asian Continental Ancestry Group/genetics
;
Autoimmunity/*genetics
;
CD4-Positive T-Lymphocytes/*immunology
;
Cytokines/genetics
;
European Continental Ancestry Group/genetics
;
Gene Expression Regulation/*immunology
;
Genetic Variation
;
Genome-Wide Association Study
;
Humans
;
Lymphocyte Activation/*genetics
;
Multigene Family
;
*Quantitative Trait Loci
;
Th17 Cells/*immunology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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