Over the past two decades, studies on pathogenic T cells have been guided by the dogma that these are mostly CD4+ Th1-type T cells and produce interferon-? (IFN-?). This concept has been revised recently because of studies showing that induction of many autoimmune diseases is not abolished in the absence of Th1 cells and that autoreactive T cells producing IL-17, but not IFN-?, play an important role in autoimmune diseases. Our preliminary studies determining the role of IL-17+ autoreactive T cells in EAU have shown that IL-17-expressing T cells can be readily identified in EAU-susceptible mice and that both IFN-? + and IL-17+ IRBP-specific T cells are uveitogenic. The observation that growth factors required for activation of IFN-?+ and IL-17+ IRBP-specific T cells IRBP-specific T cells are different and that ?? T cells play a major role in the activation of IL-17+ cells, but that they are not as important for IFN-? response, prompts us to place our emphasis on determining whether dominance of one type of pathogenic T cell is determined by the immune conditions under which T cells become activated. We will determine the activation requirements of IFN-? + and IL-17+ IRBP-specific T cells in the periphery and inside the inflamed eye and determine whether activation of two uveitogenic T cell subsets relies on different APCs and co-stimulatory molecules (Aim 1). In terms of determining the factors that are important for the activation and expansion of IL-17+ autoreactive T cells (Aims 2&3), our preliminary studies have shown that increased activation of IL-17+ T cells is frequently associated with activation of ?? TCR cells and that depletion of ?? T cells reduces induction of EAU. We will now determine whether depletion of ?? T cells prevent the Th17 uveitogenic T cells to acquire pathogenic activity and whether ?? -/- recipients will generate increased numbers of Th17-type uveitogenic T cells, if such mice are injected with a small number of ?? T subset (Aim2). We have observed that interaction between ??? and ?? T cell subsets results in the production of increased amount of IL-17. We will now determine the mechanisms that lead to reciprocal stimulation between ?? and ?? T cells and determine the role of ?? T cell subsets in immunoregulation on generation of IL17+ uveitogenic T cells. Our hypothesis is that """"""""exposure to infectious agents, such as microbial proteins, may promote ?? T cell activation. Activation of specific ?? subset(s) promotes the generation of IL17+ uveitogenic T cell;activated??? T cells may further promote the activation of ?? T cells, leading to augmented Th17 response."""""""" The continuation of this study and the clarification of the pathogenic role of, and relationship between, IFN-?+ and IL-17+ autoreactive T cells in EAU should contribute to our understanding of the mechanism of autoimmune disease pathogenesis.
Uveitis is a sight-threatening, inflammatory disease. Mice can be induced for similar disease, either by immunization of the animals with a pathogenic antigen or by adoptive transfer with uveitogenic T cells. These experimental models have been extensively used for determination of the pathogenic mechanisms that is not possible to be directly approached in humans. Our laboratory has been interested in the characterization of pathogenic T cells that cause this disease. We have developed a range of expertise in determining the cellular and molecular events crucial to the development of autoimmune disease. In this application, we propose to determine a new pathogenic T cell subset expressing interleukin-17 (IL-17).
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