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

项目概述/摘要系统性红斑狼疮（SLE）是一种自身免疫介导的炎症性疾病，病因不明。SLE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，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，我们对CD8+ T细胞在狼疮发展中的作用知之甚少，尽管事实上这些细胞组成了外周淋巴细胞的很大一部分，并通过细胞毒性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，记忆性CD8+ T细胞在SLE患者中出现扩张，这种扩张与疾病活动相关，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含义尚不清楚。从逻辑上讲，前一个问题的答案是自体抗原的慢性免疫刺激。然而，先前的研究表明，在人类狼疮中，T细胞增殖和IL-2产生对T细胞受体（TCR）触发的反应减少，这表明疾病中自身抗原驱动的反应和T细胞扩增有缺陷，而不是增强。另外，狼疮中的记忆性CD8+ T细胞扩增可能独立于抗原刺激而发生，但并非相互排斥。事实上，IL-15已成为通过促进细胞增殖和扩增来维持记忆性CD8+ T细胞（稳态）的关键细胞因子。因此，狼疮中记忆性CD8+ T细胞的扩增至少部分是由IL-15驱动的。这一观点得到了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的支持。那么狼疮细胞扩张的病理意义是什么呢？IL-15可以促进CD8+ T细胞的效应功能，包括细胞因子的产生和细胞毒性。因此，我们假设IL-15诱导SLE患者记忆性CD8+ T细胞的扩增具有病理意义。这一假设将以以下具体目标来解决：1)确定SLE患者记忆性CD8+ T细胞扩增的机制；2)探讨SLE患者记忆性CD8+ T细胞扩增的病理意义；3)前瞻性研究记忆性CD8+ T细胞的扩增是否与SLE的多种临床和生物学参数相关。证明这一假设对了解狼疮的发病机制具有重要意义，并可能导致治疗干预的新靶点。本课题的目标是研究记忆性CD8+ T细胞和细胞因子IL-15在人狼疮发病机制中的作用。这项研究的结果不仅有助于我们对狼疮的了解，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.