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

• Published in: Science (American Association for the Advancement of Science) Vol. 345; no. 6202; p. 1311
• Main Authors: Ye, Chun Jimmie, Feng, Ting, Kwon, Ho-Keun, Raj, Towfique, Wilson, Michael, 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
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 12.09.2014; The American Association for the Advancement of Science
• Subjects: Activation; African Continental Ancestry Group - genetics; Antigens; Asian Continental Ancestry Group - genetics; Autoimmune diseases; autoimmunity; Autoimmunity - genetics; Blood; CD4-Positive T-Lymphocytes - immunology; cohort studies; Cytokines - genetics; Environmental Influences; European Continental Ancestry Group - genetics; Evolution; Feedback (Response); Gene expression; Gene Expression Regulation - immunology; Gene mapping; Genes; Genetic diversity; Genetic effects; Genetic factors; Genetic Variation; Genetics; Genome-Wide Association Study; Genotype & phenotype; Genotypes; Humans; Immune response; Immune system; Individualized Instruction; Lymphocyte Activation - genetics; Lymphocytes; Meta Analysis; Mounting; Multigene Family; nationalities and ethnic groups; Pathogens; Polymorphism; Quantitative Trait Loci; RESEARCH ARTICLE SUMMARY; single nucleotide polymorphism; Specialization; T-lymphocytes; Th17 Cells - immunology; Transcripts (Written Records); Variability
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1254665

T cells are important in mounting immune responses to a host of pathogens, and they have also been implicated in autoimmune disease. By examining the variability in gene expression in stimulated T cells over time from a multi-ethnic cohort of healthy humans, Ye et al. identified specific genetic polymorphisms that explain differences among individuals in response to pathogens. Furthermore, a candidate gene approach led to the identification of a single-nucleotide polymorphism that controls the response of the autoimmune-associated IL2RA gene. This study helps us understand the degree to which immune responses are driven by the environment or by an individual's physiological or genetic factors. Science , this issue 10.1126/science.1254665 Profiles of T cell responses display genetically influenced interindividual variation. 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.