Importance of CD5 for the function of regulatory T cells

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 (lBD). The Th-I 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 oflBD. 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 CD2S, while being quiescent. In cell transfer models T-Regs have been shown to potently suppress lBD. 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 CDS, a cell surface marker present primarily on T cells and a minor subset of Bcells called B-1 cells. Based on our previous work about the negative signaling role of CDS in B-1 cells we hypothesized that CDS might negatively regulate TCR signaling in T-reg cells. This predicted that the regulatory function ofT-Regs can be augmented in the absence of CDS. Accordingly we have shown that T-Regs from CDS knockout mice are more effective in suppressing proliferation ofCD4+CD2S- effector T cells. Moreover, our preliminary studies showed that in the dextran sulfate (DSS) induced model of colitis, CDS knockout mice have a milder form of the disease which we hypothesize is due to more effective nTreg function. Our specific aims are: I. Our goal is to first to demonstrate the increased effectiveness of CDS deficient TRegs in an adoptive transfer model that consists in transferring CD4SRB+ CD4+ CD2ST- cells into Ragl-/- mice with wild type or CDS 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 lBD is reduced by inhibiting interaction of CDS with its ligand using a CDS-Ig fusion protein and/or anti-CDS antibodies. Since dendritic cells (DC) are known to modulate the development and function ofT-Regs and since CDS has been shown by us to regulate TCR mediated calcium signaling, we will test the hypothesis that interaction of DC with T-Regs via CDS and its ligand CDSL, 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 CDy/- mice to colitis induction.