Investigating the Requirement for Tbet Expression during Psoriasis

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For over a decade, a number of chronic inflammatory disorders including multiple sclerosis, rheumatoid arthritis, and psoriasis have been described as Th1 -mediated disorders because IFNy-producing CD4 T cells are prevalent in diseased patients and IFNy strongly activates macrophages, potentiating inflammation. However recent data from animal models of numerous autoimmune/chronic inflammatory disorders suggests that Th17 effector CD4 T cells are responsible for the induction of disease. Interestingly, the onset of these chronic inflammatory diseases is associated with elevated numbers of both IFNy+ and IL-17+ effector CD4 T cells at the sites of inflammation, opening the debate on the individual roles of these effector CD4 T cell populations during disease. In fact, the impact of Th1 CD4 T cells on the development of psoriasis remains unclear. Under certain experimental conditions, psoriasis can be induced by IL-12 stimulation and this pathology is associated with increased levels of IFNy, although it has been demonstrated that IFNy is not essential to drive disease. The Th1-associated transcription factors Tbet and STAT4 are required to induce some experimental models of chronic inflammation, such as EAE and colitis, even when IFNy is not. To date, little is known about the role of these transcriptional regulators during the development of psoriasis. We hypothesize that Tbet and STAT4, Th1-associated transcription factors, are necessary for the development of psoriasis mediated by CD4 T cells. We propose the following specific aims to determine the role of Tbet and STAT4 during two models of psoriasis mediated by distinct effector mechanisms. Aim 1. Tbet is required for the development of psoriasis. Aim 2. STAT4 signaling is critical for the onset of psoriasis. Collectively, these studies are designed to provide new information regarding the molecular mechanisms of CD4 T cell-mediated psoriasis. The findings from these studies may identify new potential targets for therapeutic and/or preventative strategies designed to ablate psoriasis, as well as other chronic inflammatory disorders.