Research ArticleHORMONES

Estrogen receptor α contributes to T cell–mediated autoimmune inflammation by promoting T cell activation and proliferation

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Sci. Signal.  17 Apr 2018:
Vol. 11, Issue 526, eaap9415
DOI: 10.1126/scisignal.aap9415

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Estrogen receptor stimulates T cells

Sex-linked susceptibility has been described for nearly 75% of all autoimmune disorders. More than any other risk factor discovered, being female confers the greatest risk of developing these diseases. Mohammad et al. identify a direct role for the female sex hormone estrogen in the development of autoimmune T cell responses. Deletion of estrogen receptor α (ERα) in T cells reduced disease burden in a mouse model of colitis. ERα-expressing T cells were more activated after stimulation, proliferated more, and expressed more proinflammatory cytokines than T cells lacking this receptor. Conversely, ERα-deficient T cells were more readily skewed to a regulatory T cell phenotype. Together, these data identify a role for direct sex hormone–dependent activation of T cells in autoimmune responses.

Abstract

It has long been appreciated that most autoimmune disorders are characterized by increased prevalence in females, suggesting a potential role for sex hormones in the etiology of autoimmunity. To study how estrogen receptor α (ERα) contributes to autoimmune diseases, we generated mice in which ERα was deleted specifically in T lymphocytes. We found that ERα deletion in T cells reduced their pathogenic potential in a mouse model of colitis and correlated with transcriptomic changes that affected T cell activation. ERα deletion in T cells contributed to multiple aspects of T cell function, including reducing T cell activation and proliferation and increasing the expression of Foxp3, which encodes a critical transcription factor for the differentiation and function of regulatory T cells. Thus, these data demonstrate that ERα in T cells plays an important role in inflammation and suggest that ERα-targeted immunotherapies could be used to treat autoimmune disorders.

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