Dissecting the role for IL-15 in CD8+ T cell homeostasis in human lupus

描述(由申请人提供)：项目摘要/摘要系统性红斑狼疮(SLE)是一种病因不明的自身免疫介导性炎症性疾病。系统性红斑狼疮的病理特征是对自身抗原的免疫反应改变，产生自身抗体和随后的组织损伤，其中CD4+T细胞是B细胞依赖性自身抗体反应的关键驱动因素。相反，CD8+T细胞在狼疮发病过程中的作用知之甚少，尽管CD8+T细胞构成了外周淋巴细胞的重要组成部分，并通过细胞毒和细胞因子的产生在免疫反应中发挥重要作用。最近的研究表明，在SLE患者中会出现记忆CD8+T细胞的扩张，这种扩张与疾病活动有关，我们在初步研究中重复了这一发现。这种扩张背后的机制及其影响尚不清楚。从逻辑上讲，前一个问题的答案是自身抗原的慢性免疫刺激。然而，先前的研究表明，人类狼疮患者T细胞增殖和IL-2的产生在T细胞受体(TCR)的触发下减少，这表明疾病中存在缺陷的、而不是增强的自身抗原驱动的反应和T细胞的增殖。此外，狼疮中记忆CD8+T细胞的扩增可以独立于抗原刺激而发生，但不是相互排斥的。事实上，IL-15已经成为一种关键的细胞因子，通过促进细胞的增殖和扩增来维持CD8+T细胞的记忆(动态平衡)。因此，狼疮中记忆性CD8+T细胞的扩张可能至少部分是由IL-15驱动的。SLE患者血清IL-15水平和单核细胞IL-15表达增加的研究结果支持了这一观点。那么，狼疮中这种细胞扩张的病理含义是什么？IL-15可促进CD8+T细胞的效应功能，包括细胞因子的产生和细胞毒作用。因此，我们假设在SLE患者中，IL-15诱导记忆CD8+T细胞的扩张具有病理意义。这一假说的具体目的如下：1)确定SLE患者记忆性CD8+T细胞扩张的机制；2)研究SLE患者记忆性CD8+T细胞扩张的病理意义；3)前瞻性地研究记忆性CD8+T细胞的扩张是否与SLE的各种临床和生物学参数相关。证明这一假说对理解狼疮的发病机制具有重要意义，并可能为治疗干预带来新的靶点。项目简介目前的建议的目标是调查记忆CD8+T细胞和细胞因子IL-15在人类狼疮发病机制中的作用。这项研究的结果不仅将有助于我们对狼疮的理解，而且还可能导致更好的诊断工具以及疾病监测和治疗。

DESCRIPTION (provided by applicant): Project Summary/Abstract Systemic lupus erythematosus (SLE) is an autoimmune-mediated inflammatory disease of unknown etiology. The pathologic hallmarks of SLE are altered immune responses to autoantigens with autoantibody production and subsequent tissue injury, with CD4+ T cells as critical drivers of the B cell dependent autoantibody response. Conversely, little is known about the role of CD8+ T cells in the development of lupus, despite the fact that these cells comprise a significant portion of peripheral lymphocytes and play a major role in immune responses via cytotoxicity and cytokine production. Recent studies have shown that expansion of memory CD8+ T cells occurs in patients with SLE, an expansion that is correlated with disease activity, findings that we have replicated in preliminary studies. The mechanism that underlies this expansion, and its implications, are unknown. Logic dictates that the answer to the former question is chronic immune stimulation by autoantigens. Yet previous studies have revealed that T cell proliferation and IL-2 production in response to T cell receptor (TCR) triggering is diminished in human lupus, suggesting a defective, not enhanced, autoantigen-driven response and T cell expansion in disease. Alternatively, but not mutually exclusively, memory CD8+ T cell expansion in lupus could occur independently of antigenic stimulation. Indeed, IL-15 has been emerged as a key cytokine for the maintenance (homeostasis) of memory CD8+ T cells by promotion of cell proliferation and expansion. Thus, the expansion of memory CD8+ T cells in lupus could be driven, at least in part, by IL-15. This notion is supported by the findings of an increase in serum IL-15 levels and expression of IL-15 by monocytes in patients with SLE. What then are the pathological implications of such cell expansion in lupus? IL-15 can promote effector functions of CD8+ T cells including cytokine production and cytotoxicity. Thus, we hypothesize that IL-15 induces expansion of memory CD8+ T cells with pathological implications in patients with SLE. This hypothesis will be addressed with the following specific aims: 1) Determine the mechanisms for memory CD8+ T cell expansion in patients with SLE; 2) Investigate the pathological implications of memory CD8+ T cell expansion in patients with SLE; and 3) Prospectively investigate whether expansion of memory CD8+ T cells correlates with a variety of clinical and biological parameters of SLE. Proving this hypothesis has implications for understanding the pathogenesis of lupus, and potentially could lead to new targets for therapeutic intervention.Project Narrative The goal of the current proposal is to investigate the roles of memory CD8+ T cells and the cytokine IL-15 in the pathogenesis of human lupus. The results of this study will not only aid our understanding of lupus, but will also potentially lead to better diagnostic tools as well as disease monitoring and treatment.