Cross-Talk Between Estrogen and T Cells Mediated Pathways in Lupus Pathogenesis

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Defects in the appropriate regulation of T cell function and homeostasis are fundamental to the pathogenesis of Systemic Lupus Erythematosus (SLE). Classically, SLE exhibits a striking gender bias and preferentially affects women. Although sex hormones, in particular estrogen, have been shown to affect the development and function of T cells, the molecular pathways by which the hormonal milieu modulates T cell responses are largely unknown. Our laboratory has cloned a novel molecule, termed IBP, which is highly expressed in T cells and is a novel member of a unique family of Rho GTPase activators, which is activated upon TCR engagement. Our studies in mice deficient for IBP have revealed that lack of IBP leads to the development of a lupus-like syndrome characterized by the accumulation of effector T cells and IgG+ B cells, profound hypergammaglobulinemia, autoantibody production, proteinuria and glomerulonephritis. Like human SLE, development of these manifestations primarily affects the female gender. Although IBP is highly expressed in lymphoid cells, IBP can also be found in epithelial cells from the mammary gland and our studies indicate that its expression in both breast epithelium and immune cells can be regulated by estrogen. Furthermore, we have recently found that expression of ERa is downregulated upon T cell stimulation in wt T cells but not in IBP deficient T cells. Taken all together these findings have led us to hypothesize that IBP is an estrogen regulated gene that controls a regulatory feedback loop aimed at restricting estrogen signaling during the activation of T cells. The major goal of this proposal is to dissect the cross-talk between IBP and sex hormones and determine whether IBP can be utilized as a novel molecular target to understand, at a mechanistic level, how sex hormones affect T cell physiology and pathophysiology. Specifically, we will: 1. Assess the mechanisms by which IBP controls the expression of ERa in T cells. 2. Investigate the role of estrogen on the lupus-like syndrome that develops in the absence of IBP.