IL-4 Potentiates T Cell Death in Autoimmune Arthritis

描述(由申请人提供)： T细胞活化诱导的细胞死亡(AICD)是外周免疫耐受的主要机制之一。T细胞通过其抗原受体(TCR)反复刺激，诱导T细胞表面Fas和Fas配体(FasL)共表达，FasL相互作用导致T细胞“自杀”或“自杀性”。蛋白多糖(PG)诱导的关节炎(PGIA)是用PG软骨系统免疫BALB/c小鼠建立的一种新的自身免疫性小鼠模型。这种疾病的发展是基于免疫遗传易感BALB/c小鼠的人和小鼠(自身)软骨PGs之间的交叉反应。在这个自身免疫性关节炎模型中，外周血CD4+T细胞在体外对TCR刺激的异常增殖被发现与关节炎小鼠低水平的AICD和高比例的干扰素-γ/白介素4(IL-4)有关。此外，与野生型(WT)BALB/c小鼠相比，IL-4缺陷小鼠的PGIA发生率和严重程度增加，而给WT BALB/c小鼠注射IL-4则显著减少疾病。最近的研究表明，IL-4通过下调Fas相关死亡域样IL-1β转换酶抑制蛋白(FLIP)的表达和上调FasL的表达来促进AICD，这些作用是通过上调T细胞对IL-2的敏感性实现的。这些发现共同表明，关节炎小鼠的辅助性T细胞1(THL)可能对AICD具有抵抗力，这可能归因于较高水平的翻转表达。这项研究的总体假设是，IL-4可能促进PGIA中自身反应性Th1细胞的外周缺失。IL-4的缺乏可能促进自身反应性Th1细胞在外周聚集，导致自身耐受性的崩溃，并通过抗原驱动的机制引发滑膜关节的炎症。在这项研究方案中，描述了研究IL-4是否以及如何影响PGIA中CD4+T细胞的AICD。具体而言，他们将确定：(I)IL-4缺乏导致PGIA患者IL-4缺陷小鼠CD4+T细胞Fas介导的AICD严重受损；(Ii)IL-4缺陷PGIA小鼠CD4+T细胞AICD受Flip和/或FasL异常表达的调节；(Iii)IL-4介导的Janus kianses/信号转导和转录激活-6信号通路使PGIA患者自身反应性T细胞对AICD的敏感性增加；以及(Iv)IL-4通过调节细胞周期进程调节自身反应性T细胞对AICD的敏感性。

DESCRIPTION (provided by applicant): Activation-induced cell death (AICD) in T cells is one of the major mechanisms for peripheral tolerance. Repeated stimulation of T cells via their antigen receptor (TCR) induces coexpression of Fas and Fas ligand (FasL) on the surface of T cells and the 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 BALB/c mice with cartilage PG. The development of the disease is based upon cross-reactive immune responses between the immunizing human and mouse (self) cartilage PGs in genetically susceptible BALB/c mice. In this autoimmune arthritis model, an aberrant proliferation of peripheral CD4+ T cells in vitro in response to TCR stimulation is found to be associated with low levels of AICD and a high ratio of interferon-gamma to interleukin-4 (IL-4) in arthritic mice. Moreover, the incidence and severity of PGIA is augmented in IL-4-deficient mice in comparison to wild-type (WT) BALB/c mice, whereas administration of IL-4 to WT BALB/c mice significantly reduces disease. Recent studies indicate that IL-4 can promote AICD by down regulating expression of Fas-associated death domain-like IL1 beta-converting enzyme inhibitory protein (FLIP) and up regulating FasL expression, and these effects are achieved via the up regulation of T cell sensitivity to IL-2. These findings together suggest that T helper 1 (Thl) cells from arthritic mice may be resistant to AICD which may be ascribed to a higher level of FLIP expression. The overall hypothesis of this research proposal is that IL-4 may potentiate peripheral deletion of autoreactive Thl cells in PGIA. The absence of IL-4 may facilitate the accumulation of autoreactive Thl cells in the periphery, leading to the breakdown of self-tolerance, and provoking inflammation in synovial joints by an antigen-driven mechanism. In this research proposal, studies are described to investigate whether and how IL-4 affects AICD of CD4+ T cells in PGIA. Specifically, they will determine whether (i) lack of IL4 results in a severely impaired Fas-mediated AICD of CD4+ T cells in IL-4deficient mice with PGIA; (ii) defective AICD of CD4 T cells in IL-4-deficient mice with PGIA is regulated by an aberrant expression of FLIP and/or FasL; (iii) IL-4-mediated Janus kianses/signal transducer and activator of transcription-6 signaling pathway confers the susceptibility of autoreactive T cells to AICD in PGIA; and (iv) IL-4 regulates the susceptibility of autoreactive T cells to AICD by adjusting the cell cycle progression.