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。通过T细胞的抗原受体（TCR）反复刺激T细胞，诱导T细胞表面Fas和Fas配体（FasL）的共表达，并且FasL相互作用导致T细胞的“自杀”或“自相残杀”。蛋白多糖（PG）诱导的关节炎（PGIA）是一种新型的自身免疫性小鼠模型，由软骨PG全身免疫BALB/c小鼠诱导，其发病机制是由免疫的人和小鼠（自身）软骨PG在遗传易感的BALB/c小鼠体内产生交叉免疫反应。在这种自身免疫性关节炎模型中，发现外周CD 4 + T细胞在体外响应于TCR刺激的异常增殖与关节炎小鼠中低水平的AICD和高比例的干扰素-γ与白细胞介素-4（IL-4）相关。此外，与野生型（WT）BALB/c小鼠相比，IL-4缺陷小鼠中PGIA的发生率和严重程度增加，而向WT BALB/c小鼠施用IL-4显著降低疾病。最近的研究表明，IL-4可通过下调Fas相关死亡结构域样IL 1 β转化酶抑制蛋白（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的敏感性来实现的。这些发现共同表明，T辅助1（Th 1）细胞从关节炎小鼠可能是耐AICD，这可能归因于较高水平的FLIP表达。本研究建议的总体假设是IL-4可增强PGIA中自身反应性Thl细胞的外周缺失。IL-4的缺乏可促进自身反应性Thl细胞在外周中的积累，导致自身耐受性的破坏，并通过抗原驱动机制引起滑膜关节中的炎症。在本研究计划中，研究IL-4是否以及如何影响PGIA中CD 4 + T细胞的AICD。具体地说，他们将确定（i）IL-4缺乏是否会导致PGIA的IL-4缺乏小鼠中Fas介导的CD 4 + T细胞的AICD严重受损;（ii）PGIA的IL-4缺乏小鼠中CD 4 T细胞的缺陷性AICD是否受到FLIP和/或FasL异常表达的调节;（iii）IL-4介导的Janus kianses/信号转导子和转录激活子-6信号通路赋予PGIA中自身反应性T细胞对AICD的易感性;和（iv）IL-4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。

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.