Importance of CD5 for the function of regulatory T cells

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DESCRIPTION (provided by applicant): Studies in animal models have shown that both the adaptive and the innate immune system have a definite role in inducing intestinal inflammation, a hallmark of inflammatory bowel diseases (IBD). The Th-1 and Th-17 type T cells have a dominant role in Crohn's disease while the Th-2 type T cells appear to be more important for ulcerative colitis. Studies in the past decade have established the unequivocal role of regulatory T cells (T-Reg) in controlling the development of IBD. The T-regs are a recently discovered subset of CD4+ T cells that have a profound ability to suppress the effector function of helper T cells. They are characterized by expression of a transcription factor Foxp3 and CD25, while being quiescent. In cell transfer models T-Regs have been shown to potently suppress IBD. Yet there have not been any methods to augment the function of regulatory T cells in vivo which could have therapeutic potential. T-Regs express CD5, a cell surface marker present primarily on T cells and a minor subset of B- cells called B-1 cells. Based on our previous work about the negative signaling role of CD5 in B-1 cells we hypothesized that CD5 might negatively regulate TCR signaling in T-reg cells. This predicted that the regulatory function of T-Regs can be augmented in the absence of CD5. Accordingly we have shown that T-Regs from CD5 knockout mice are more effective in suppressing proliferation of CD4+CD25- effector T cells. Moreover, our preliminary studies showed that in the dextran sulfate (DSS) induced model of colitis, CD5 knockout mice have a milder form of the disease which we hypothesize is due to more effective nTreg function. Our specific aims are: 1. Our goal is to first to demonstrate the increased effectiveness of CD5 deficient T- Regs in an adoptive transfer model that consists in transferring CD45RB+ CD4+ CD25- T-cells into Rag1-/- mice with wild type or CD5 knockout T-Regs. 2. To develop a wild type animal model in which nTreg function can be enhanced. Here we will determine if development of IBD is reduced by inhibiting interaction of CD5 with its ligand using a CD5-Ig fusion protein and/or anti-CD5 antibodies. Since dendritic cells (DC) are known to modulate the development and function of T-Regs and since CD5 has been shown by us to regulate TCR mediated calcium signaling, we will test the hypothesis that interaction of DC with T-Regs via CD5 and its ligand CD5L, affects T-reg function. 3. To develop an alternate model of colitis to evaluate the role of non T cells in the inreased resistance of CD5-/- mice to colitis induction. PUBLIC HEALTH RELEVACE We have found that CD5, a molecule generally expressed on all T cells, decreases regulatory T cell (T-reg) function and that T-Regs from mice in which CD5 is genetically deleted are more potent regulators of immune response. Here we plan to demonstrate that in an in vivo animal model of colitis induced by disease causing T cells, the function of T-Regs is regulated by CD5 expression.