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

剖析 IL-15 在人类狼疮 CD8 T 细胞稳态中的作用

基本信息

批准号：
8212122
负责人：
Joseph Edgar Craft
金额：
$ 40.55万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2013-01-31
项目状态：
已结题

项目摘要

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.

系统性红斑狼疮（SLE）是一种病因不明的自身免疫介导的炎症性疾病。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，产生自身抗体并随后出现组织损伤，其中CD 4 + 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，关于CD 8 + T细胞在狼疮发展中的作用知之甚少，尽管这些细胞构成外周淋巴细胞的重要部分，并通过细胞毒性和细胞因子产生在免疫应答中发挥主要作用。最近的研究表明，记忆性CD 8 + T细胞的扩增发生在SLE患者中，这种扩增与疾病活动相关，我们在初步研究中复制了这一发现。这种扩张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，先前的研究已经揭示，在人类狼疮中，响应于T细胞受体（TCR）触发的T细胞增殖和IL-2产生减少，这表明疾病中的自身抗原驱动的应答和T细胞扩增有缺陷，而不是增强。或者，但不相互排斥，记忆CD 8 + T细胞的扩展在狼疮可以发生独立的抗原刺激。事实上，IL-15已经成为通过促进细胞增殖和扩增来维持（稳态）记忆性CD 8 + T细胞的关键细胞因子。因此，狼疮中记忆性CD 8 + T细胞的扩增可能至少部分由IL-15驱动。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，狼疮中这种细胞扩张的病理学意义是什么呢？IL-15可以促进CD 8 + T细胞的效应子功能，包括细胞因子产生和细胞毒性。因此，我们假设IL-15诱导SLE患者记忆性CD 8 + T细胞的扩增，并具有病理学意义。该假说将通过以下具体目标来解决：1）确定SLE患者记忆性CD 8 + T细胞扩增的机制; 2）研究SLE患者记忆性CD 8 + T细胞扩增的病理学意义; 3）初步研究记忆性CD 8 + T细胞扩增是否与SLE的各种临床和生物学参数相关。证明这一假设的意义，了解狼疮的发病机制，并可能导致新的目标，治疗intervention.Project叙述目前的建议的目标是调查的角色，记忆CD 8 + T细胞和细胞因子IL-15在人类狼疮的发病机制。这项研究的结果不仅有助于我们了解狼疮，而且还可能导致更好的诊断工具以及疾病监测和治疗。