CD95 AND CD95L IN CD4+ T CELL REGULATION AND FUNCTION

来自人类和动物模型肿瘤系统的证据表明 将自身反应性限制为组织特异性的调节元件 抗原也限制了免疫反应的有效性 已确诊的肿瘤。这项提案的目标是定义 CD95(Fas)及其配体(CD95L)在CD_4~+淋巴细胞调节和调节中的作用 功能。这两种蛋白在活化后的T细胞上均有表达 CD95稳定表达，CD95L瞬时表达 对抗原刺激T细胞受体(TCR)的反应。小鼠带有 这两种基因产物(LPR和GLD)出现表达缺陷 淋巴增殖性疾病，在适当的遗传背景下， 自发性自身免疫，与人类有许多相似之处的肾脏疾病 系统性红斑狼疮(SLE)。ITS对CD95的刺激作用 配体可导致T细胞自杀或被T细胞谋杀 邻近的表达CD95的细胞。 我们已经获得的证据表明，CD95途径不仅可以是一种 间接致病原因通过其免疫调节作用，也 诱发性自身免疫性疾病发病的直接原因 实验性变态反应性脑脊髓炎(EAE) 疾病多发性硬化(MS)。出乎意料的是，这些突变改善了 而不是加剧这种自身免疫综合症。迄今为止的实验 提示T细胞使用CD95依赖的杀伤途径破坏中枢神经系统 元素。该提案的目标1将在体内用新的、 我们与抗CNS、TCR协同产生的同源菌株 其他人生产的转基因小鼠。CD95依赖的必然结果 发病模型是T细胞必须使用一种旁观者裂解的形式 中枢神经系统细胞。在EAE中受损的关键细胞不表达适当的 诱导CD4+CD95L的抗原提呈分子(MHC-II类) 细胞。我们提供了第一个证据证明一种可溶的、不稳定的、但 功能形式的小鼠CD95L是这个旁观者中的效应者 并不是所有的抗原提呈细胞(APC)都有能力 刺激旁观者裂解，即使它们可以刺激T细胞 影响他们自己的CD95依赖死亡。Aim#2将阐明APC 刺激有效的旁观者裂解所需的分子。目标#3将 探索环境因素和遗传因素之间的关系 产生狼疮样综合征所需的敏感度和抵抗力 携带LPR突变的遗传背景。

Evidence from both human and animal model tumor systems has demonstrated that the regulatory elements limiting autoreactivity to tissue-specific antigens also limits the effectiveness of the immune response to established tumors. The goal of this proposal is to define the role of CD95 (Fas) and its ligand (CD95L) in CD4+ lymphocyte regulation and function. Both proteins are expressed on T cells after activation with CD95 being stably expressed, and CD95L being transiently expressed in response to antigen stimulation of the T cell receptor (TCR). Mice with defective expression of these two gene products (lpr and gld) develop lymphoproliferative disease and, on the appropriate genetic background, a spontaneous autoimmune, renal disease with many similarities to the human disease systemic lupus erythematosus (SLE). Stimulation of CD95 by its ligand can cause either suicide of the T cell or murder by the T cell of an adjacent, CD95-expressing cell. We have obtained evidence that the CD95 pathway can be not only an indirect cause of pathogenesis through its immunoregulatory role, but also a direct cause of pathogenesis in the induced autoimmune disease experimental allergic encephalomyelitis (EAE), a model of the human disease multiple sclerosis (MS). Unexpectedly, the mutations ameliorate rather than exacerbate this autoimmune syndrome. The experiments to date indicate that T cells use the CD95-dependent murder pathway to destroy CNS elements. AIM #1 of this proposal will test this model in vivo with new, congenic strains that we have produced in concert with anti-CNS, TCR transgenic mice produced by others. A corollary of the CD95-dependent pathogenesis model is that T cells must use a form of bystander lysis on CNS cells. The crucial cells damaged in EAE do not express appropriate antigen presenting molecules (MHC class II) for CD95L induction on CD4+ cells. We provide the first evidence that a soluble, unstable, but functional form of the murine CD95L is the effector in this bystander lysis and that not all antigen presenting cells (APC) are capable of stimulating bystander lysis even though they can stimulate the T cells to effect their own CD95-dependent death. AIM #2 will elucidate the APC molecules necessary to stimulate effective bystander lysis. AIM #3 will explore the relationship between environmental and genetic factors necessary to produce the lupus-like syndrome on sensitive and resistant genetic backgrounds carrying the lpr mutation.