IL-7 Biology and Role in Systemic Autoimmunity

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DESCRIPTION (provided by applicant): Cytokines constitute a vast and complex network of molecules involved in almost every aspect of the immune system. Among these, IL-7 has emerged as a major T cell trophic cytokine affecting survival and homeostasis of T cells, processes that are highly disturbed in lupus-associated systemic autoimmunity. Consequently, we have made a concerted effort to define the role of IL-7 in the pathogenesis of this disease in mouse models. Our published and preliminary findings showed that blockade of IL-7R signaling effectively reduces disease severity in both murine lupus and EAE. Brief application of this treatment preferentially eliminated autoreactive T cells undergoing activation and, strikingly, additional studies showed that IL-7 provides a third signal beyond TCR and constimulatory receptor engagement to enhance activation and proliferation of low-affinity autoreactive T cells. Moreover, lymphadenopathy in murine lupus was associated with expansion of IL-7-producing lymphoid stromal cells, specifically fibroblastic reticular cells (FRCs). Accordingly, in this proposal, Specific Aim 1 will address the biochemical basis for IL-7-mediated enhancement of T cell activation, proliferation, survival, and metabolic status, while Specific Aim 2 will investigae the location and frequency of cellular sources of IL-7 in secondary lymphoid organs, the influence of inflammation-promoting TLRs and type I IFNs on IL-7 production and transcriptional status of these cells, and disease-modifying effects of genetic modifications that ablate IL-7 production by stromal and lymphatic endothelial cells (LECs). These biologic and mechanistic studies on IL-7 and its cellular producers will reveal novel aspects of autoimmune disease pathogenesis and may identify new therapeutic targets for intervention.