Research Article

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

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Science  12 Sep 2014:
Vol. 345, Issue 6202, 1254665
DOI: 10.1126/science.1254665

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Structured Abstract


The activation of CD4+ T lymphocytes by antigen initiates adaptive immune responses, amplifying rare antigen-specific clones and leading to functional specialization of effector T cells, in particular through the spectrum of cytokines they produce. Pathogens have exerted selective pressure during recent human evolution and migrations, but selection for a type of response that is optimal against one microbe class could carry a price in less-effective responses to other microbes or in impaired self-tolerance and autoimmune disease. Little is known about interindividual variation in the responsiveness of human CD4+ T cells and how genetic variation affects the tone and intensity of T cell responses in human individuals.

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Characterizing the variation in T cell response. A total of 348 individuals from the ImmVar cohort donated blood for CD4+ T cell isolation and genotyping. The T cells were subsequently activated to mimic the recognition of the cognate antigen. The variability in adaptive immune response, which may have genetic and nongenetic components, was characterized by profiling the response of activated T cells. A computational analysis uncovered genetic drivers for this variation and pinpointed molecular mechanisms by which they may act.


As the third arm of the ImmVar project, we performed a rigorously controlled analysis of the responses of human blood CD4+ T cells to activation in unbiased conditions or in a culture regimen that promotes differentiation to the T helper 17 cell (TH17) phenotype. To permit an appreciation of the breadth of variation across humans, we investigated these responses in a cohort of 348 healthy human volunteers representing three different ancestries (African, Asian, and European). Responses to activation were evaluated by gene expression profiling, focused on the transcripts that best represent the response, its variability, and its functional consequences. Relating these data to dense single-nucleotide polymorphism genotypes from the participants, we identified the genetic contributions to this variation by using heritability analysis and fine-mapped previously unknown expression quantitative trait loci (eQTLs) that control these responses by using trans-ethnic meta-analysis.


We observed a high degree of interindividual variability, much of which was reproducible for a given subject. This variability followed complex patterns and did not reduce simply to dominant TH1, 2, or 17 types. We identified 39 loci associated in cis with gene activation in T cells. These explained on average 25% of the repeatable variation, but a major element could not be ascribed to simple genetic effects, instead reflecting environmental influences, immunologic history, or complex integration of network regulation. Of activation-induced genes, cytokines showed the most variability, but with little or no cis genetic control, in contrast to cytokine receptors, which were less variable but for which several eQTLs were detected. Ancestry of the donors markedly influenced T cell responses, with stronger TH17 being associated with African descent. We fine-mapped and validated experimentally a single-base variant that modulates binding of the transcription factor YY1 and hence the activity of an enhancer element controlling the autoimmune-associated IL2RA gene, affecting its activity in activated but not regulatory T cells.


Echoing the linked ImmVar studies, we find that the relevant cell type and context are essential for discovering the genetic drivers of cell-specific responses and of connected autoinflammatory diseases. Our study lays the groundwork for further explorations into the relative contributions of genes and their environment on immunological processes, which should aid in our understanding of autoimmune disease and its genetic underpinnings.

Response to pathogens is in the genes

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


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.

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