ALTERED T-CELL ACTIVATION IN AUTOIMMUNE ARTHRITIS

过度刺激的T细胞的激活诱导的细胞死亡（AICD）已被认为是稳态和预防自身免疫的重要机制。通过T细胞抗原受体（TCR）反复刺激T细胞，可诱导T细胞表面Fas和Fas配体（FasL）共表达，Fas与FasL相互作用导致T细胞“自杀”或“自相残杀”。蛋白多糖诱导的关节炎（Proteoglycan，PG）是一种新型的自身免疫性关节炎模型。在该模型中，外周血CD 4 + T细胞对TCR刺激的异常增殖反应被抑制。 与关节炎小鼠中低水平的AICD和高比例的干扰素（IFN）-γ与白细胞介素（IL）-4相关。PGIA小鼠的AICD缺陷和CD 4 + T细胞过度增殖可能归因于未能诱导细胞Fas相关死亡结构域（FADD）样IL-1 β转化酶（FLICE）抑制蛋白（c-FLIP）的降解。与野生型（Wt）BALB/c小鼠相比，IL-4缺陷（IL-4-/-）小鼠中PGIA的发生率和严重程度增加，而对BALB/c小鼠施用IL-4可大大降低疾病。此外，PG-致敏的IL-4-/-CD 4 + T细胞不能经历凋亡。基于这些观察结果，我们假设IL-4的缺失导致诱导c-FLIP降解的失败，这反过来又导致AICD缺陷和外周中自身反应性Th 1型细胞的过度增殖，从而导致PGIA的发展。为了证实我们的假设，我们提出三个 具体目标：（1）我们将确定IL-4缺失是否以及如何导致PGIA小鼠体内CD 4 + T细胞的积聚：（2）我们将研究c-FLIP是否调节PGIA小鼠中致关节炎性CD 4 + T细胞的过度增殖和缺陷AICD;（3）确定IL-4是否通过调节细胞周期进程来调节自身反应性T细胞对AICD的易感性，并研究IL-4是否通过控制c-FLIP表达来调节细胞周期进程。拟议的研究所产生的信息将增强我们对IL-4的生物学功能的理解，并将为自身免疫性关节炎的新治疗方法的发展提供启示。

Activation-induced cell death (AICD) of over-stimulated T cells has been proposed to be an important mechanism in homeostasis and the prevention of autoimmunity. Repeated stimulation of T cells through T cell antigen receptor (TCR) induces co-expression of Fas and Fas ligand (FasL) on the surface of T cells, and the Fas-FasL interaction leads to the "suicide" or "fratricide" of T cells. Proteoglycan (PG)-induced arthritis (PGIA) is a novel autoimmune murine model induced by systemic immunization of mice with cartilage PG. In this model, an aberrant proliferation of peripheral CD4+ T cells in vitro in response to TCR stimulation was associated with low levels of AICD and a high ratio of interferon (IFN)-gamma to interleukin (IL)-4 in arthritic mice. The defective AICD and hyper-proliferation of CD4+ T cells in mice with PGIA may be ascribed to failure of inducing degradation of cellular Fas-associated death domain (FADD)-like IL-1beta-converting enzyme (FLICE)-inhibitory protein (c-FLIP). The incidence and severity of PGIA is augmented in IL-4-deficient (IL-4-/-) mice in comparison to wild-type (Wt) BALB/c mice, whereas administration of IL-4 to BALB/c mice greatly reduces disease. Moreover, PG-primed IL-4-/- CD4 + T cells fail to undergo apoptosis. Based upon these observations, we hypothesize that loss of IL-4 leads to a failure of inducing c-FLIP degradation which in turn results in defective AICD and hyperproliferation of autoreactive Th1-type cells in the periphery, thus leading to the development of PGIA. To confirm our hypothesis, we propose three specific aims: (1) We will define whether and how loss of IL-4 results in accumulation of CD4+ T cells in IL-4-/- mice with PGIA in vivo; (2) We will investigate whether c-FLIP regulates hyper-proliferation and defective AICD of arthritogenic CD4+ T cells in IL-4-/- mice with PGIA; and (3) We will determine whether IL-4 regulates the susceptibility of autoreactive T cells to AICD by adjusting cell cycle progression, and investigate whether IL-4 regulates cell cycle progression through controlling c-FLIP expression. The information generated by the proposed studies will enhance our understanding of the biological function of IL-4 and will shed light on the development of novel therapeutic approaches to autoimmune arthritis.