Lymphotoxin(LT)-alphabeta LIGHT cytokine systems have emerged as critical factors regulating the development and effector functions of innate and adaptive immune systems. This project period is focused on the actions of LIGHT and LTalphabeta as regulators of lymphocyte activation and survival. Beyond the recognized role of LTalphabeta in lymphoid organogenesis, new results indicate that LTalphabeta and LIGHT are essential for survival of T and B lymphocytes in response to a viral pathogen. Constitutive expression of LIGHT as a transgene in T cells leads to a profound cell-mediated, intestinal inflammatory disease, but with lymphoid abnormalities. Further, LIGHT is a candidate susceptibility locus for inflammatory bowel disease in humans providing strong circumstantial evidence linking these cytokines to a human autoimmune disease. Additionally, ligation of HVEM leads to negative regulation of T cell responses that can override CD28 costimulation.
Three specific aims are proposed to elucidate their roles in T cell activation and survival.
The first aim develops a transferable model of intestinal inflammation by expression of LIGHT in splenic T cells via a feline immunodeficiency virus (FIV; lentivirus) vector. T cells are adoptively transferred into HVEM-/- and LTbetaR-/- mice to determine the receptor basis of the inflammatory phenotype. The functionality of the distinct physical forms of LIGHT will be examined with this FIV model. The regulatory elements and mutations/polymorphisms that control human LIGHT gene expression and protein function will be defined using bioinformatic and molecular genetic approaches. Monoclonal Abs to mouse HVEM and LTbetaR were developed that function as immune modulators.
The second aim focuses on the use of these antibodies to directly probe the functions of HVEM in physiological settings, including the 5CC7 TCR-Tg mice and the CD4+CD45Rb(hi) adoptive transfer model of inflammatory mucosal disease. Finally, the signaling pathways induced by HVEM will be investigated using biochemical and genetic systems to elucidate the mechanism of negative signaling in T cells. The specific effector molecules induced by LTbetaR and HVEM signaling pathways, identified by their functional properties or through DNA array analysis, will be tested using virus infection and LIGHT-induced intestinal inflammation models. Together these aims will provide new insight into the physiologic role of the LTalphabeta and LIGHT cytokine systems in cell-mediated inflammatory reactions and pathogenesis of human autoimmune disease.
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