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， 将自身反应性限制在组织特异性 抗原也限制了免疫反应的有效性， 建立肿瘤。 本提案的目的是确定以下方面的作用： CD95（Fas）及其配体（CD95L）在CD4+淋巴细胞调节中的作用， 功能 这两种蛋白质在活化后在T细胞上表达， CD95稳定表达，CD95L瞬时表达。 对T细胞受体（TCR）的抗原刺激的应答。 小鼠 这两种基因产物（lpr和gld）的缺陷表达发展 淋巴增生性疾病，并在适当的遗传背景下， 自发性自身免疫性肾病与人类有许多相似之处 系统性红斑狼疮（SLE） CD95的刺激作用 配体可以导致T细胞自杀或被T细胞谋杀， 相邻的表达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 通过其免疫调节作用间接致病，而且 诱发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），一种人类 多发性硬化症（MS）。 出乎意料的是，突变改善了 而不是加重自身免疫综合症 迄今为止的实验 表明T细胞使用CD95依赖性谋杀途径来破坏CNS 元素 本提案的AIM #1将在体内测试该模型， 我们生产的与抗CNS，TCR 转基因小鼠。 CD95依赖性 发病机制模型是T细胞必须使用一种旁观者溶解形式， CNS细胞。EAE中受损的关键细胞不能表达适当的 用于在CD4+上诱导CD95L的抗原呈递分子（MHC II类） 细胞 我们提供了第一个证据，证明一个可溶的，不稳定的，但 鼠CD95L的功能形式是该旁观者中的效应子 并不是所有的抗原呈递细胞（APC）都能够 刺激旁观者溶解，即使它们可以刺激T细胞， 导致自身CD95依赖性死亡。 目标#2将阐明APC 刺激有效的旁观者裂解所必需的分子。 目标#3将 探索环境和遗传因素之间的关系 产生狼疮样综合征所必需的敏感和耐药 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.