IL-7 Biology and Role in Systemic Autoimmunity

描述（由申请人提供）：细胞因子构成了一个庞大而复杂的分子网络，几乎涉及免疫系统的各个方面。其中，IL-7已成为影响T细胞的存活和稳态的主要T细胞营养细胞因子，这些过程在狼疮相关的系统性自身免疫中受到高度干扰。因此，我们已经做出了一致的努力来确定IL-7在小鼠模型中这种疾病的发病机制中的作用。我们发表的和初步的研究结果表明，IL-7 R信号传导的阻断有效地降低了狼疮和EAE的疾病严重程度。这种治疗的短暂应用优先消除了经历活化的自身反应性T细胞，并且引人注目的是，另外的研究表明IL-7提供了TCR和共刺激受体接合之外的第三信号，以增强低亲和力自身反应性T细胞的活化和增殖。此外，淋巴结病在小鼠狼疮与IL-7产生淋巴基质细胞，特别是成纤维细胞网状细胞（FRC）的扩张。因此，在该提案中，特异性目标1将解决IL-7介导的T细胞活化、增殖、存活和代谢状态增强的生物化学基础，而特异性目标2将研究IL-7在次级淋巴器官中的细胞来源的位置和频率，促炎TLR和I型IFN对这些细胞的IL-7产生和转录状态的影响，以及消除基质和淋巴内皮细胞（LEC）产生IL-7的遗传修饰的疾病修饰作用。这些关于IL-7及其细胞产生者的生物学和机制研究将揭示自身免疫性疾病发病机制的新方面，并可能确定新的干预治疗靶点。

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.