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已经证明

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.