Sexually dimorphic control of regulatory T cell function and autoimmunity protection through B7-H1 and estrogen signals (123.50)

Abstract CD4+CD25hi regulatory T cells (Tregs) mediate peripheral tolerance and defend against autoimmunity. Among immune sexual dimorphisms, autoimmunity is more common in females but underlying mechanism(s) are poorly understood. We show that B7-H1 signals dampen estrogen-driven Treg mTOR activation through estrogen receptor beta, reducing Treg function independent of PTEN. Poorly functional Tregs from B7-H1 deficient hosts appeared phenotypically normal and did not produce IL-17. B7-H1-deficient female mice (but not males or WT of either sex) were prone to anti-CTLA-4-induced autoimmunity. Autoimmune propensity was rescued by estrogen withdrawal or B7-H1-sufficient dendritic cell transfer. B7-H1-mediated effects on estrogen signals were also mediated by B or T lymphocytes or monocytes, and occurred during induced Treg generation, with no effect on differentiated Tregs. CD80 and PD-1 were not ligands for these effects nor was Treg B7-H1 expression required. Estrogen affected male Tregs in vitro and in vivo provided B7-H1 was blocked. Strikingly, B7-H1 and estrogen did not affect thymic Treg differentiation or function, suggesting differential control of natural Tregs and a potential role for induced Tregs in autoimmunity protection. Similar Treg results were seen in BL6 and Balb/c mice. We thus show a mechanistic basis for the female propensity to autoimmunity, and data are consistent with proposed roles for B7-H1 in female-predominant autoimmune disorders, particularly lupus.