title: Intersection of population variation and autoimmunity genetics in human T cell activation.
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.
authors.affiliation: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.
authors.forename: Chun Jimmie
authors.initials: CJ
authors.lastname: Ye
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Feng
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ho-Keun
authors.initials: HK
authors.lastname: Kwon
authors.affiliation: 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.
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Wilson
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Asinovski
authors.affiliation: 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.
authors.forename: Cristin
authors.initials: C
authors.lastname: McCabe
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Frohlich
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hyun-il
authors.initials: HI
authors.lastname: Paik
authors.affiliation: Department of Medicine Lung Biology Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Zaitlen
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.affiliation: Section of Genetic Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Stranger
authors.affiliation: 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.
authors.forename: Philip
authors.initials: P
authors.lastname: De Jager
authors.affiliation: 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.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.affiliation: 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.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: 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.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
mesh_terms: D044466:Asian People / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics*; D044383:Black People / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics*; D005810:Multigene Family; D040641:Quantitative Trait Loci; D058504:Th17 Cells / Q000276:immunology*; D044465:White People / Q000235:genetics
chemical_list: D016207:Cytokines