Interleukin-17-producing T cell (Th17) is an important T-helper subset characterized by a unique transcriptional program regulated through activation of STAT3 pathways by IL-6, IL-21 and IL-23 (10-12). Although much is known about the role of STAT3 in regulating differentiation of Th17 cells and their role in Th17-mediated autoimmune diseases, its function in other lymphocyte subsets is not well understood. In this study, we have investigated: (i) mechanisms that may explain the frequent involvement of STAT3 and Th17 cells in the etiology of organ-specific autoimmune diseases, such as uveitis and multiple sclerosis; (ii) Whether STAT3 has effects on the proliferation, survival or effector functions of other T cell subsets. A major focus of our study is on proteins that regulate the initiation, intensity and duration of STAT signals during inflammation. Suppressors of cytokine signaling (SOCS) proteins are important negative regulators of JAK/STAT signaling pathways. We have generated mice with SOCS3 deletion in CD4 T cell compartment (CD4-SOCS3KO) and shown that the CD4-SOCS3KO mice are protected from acute and chronic uveitis. We have also genetically engineered cell-penetrating SOCS proteins (membrane-translocating sequence (MTS)-SOCS1, MTS-SOCS3) and demonstrated their inhibitory effects on inflammatory cytokines such as IL-6 and interferon gamma (IFN-g) that mediate their biological activities through activation of JAK/STAT pathways. We have also shown that while SOCS1 mimetic peptide mitigates uveitis, SOCS antagonists confer protection against herpes simplex infection of the eye.
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