The recently discovered Tim (T cell Immunoglobulin and Mucin domain) gene family has emerged as an important player in immune regulation. We identified Tim-3 as a molecule expressed specifically on CD4+ Th1 but not Th2 cells. The interaction of Tim-3 with its ligand, galectin-9, triggers cell death in Th1 cells, thereby dampening Th1 immunity. Tim-3 is also expressed on CDS* Tc1 but not Tc2 cells. However, whether Tim-3 similarly regulates Tc1 effector cells has not been examined. Interestingly, we have now found that Tim-3 is expressed on all dendritic cells (DCs), the major antigen presenting cells (APCs) of the immune system and on central nervous system (CNS) microglia, the local APCs in the CNS. These observations raise the possibility that Tim-3 may regulate the adaptive immune response via its expression on APCs. Indeed, we have found that Tim-3, contrary to its role in dampening Th1 immunity via its expression on Th1 cells, may promote Th1 immunity via its expression on APCs. This suggests that Tim-3 may serve opposing roles in the innate and adaptive immune systems. Tim-1 is expressed on all activated CD4+ T cells with Th2 cells expressing slightly higher levels relative to Th1 cells. Tim-1 can function as a costimulatory molecule and appears to be important in the induction of T cell tolerance. These observations support an important role for Tim-1-mediated regulation of CD4+ T cell responses. However, the effects of Tim-1 in Th1 cells, and the newly identified subset of Th-17 cells, have not been examined. In addition, we have found that Tim-1 is expressed on all CDS* T cells directly ex vivo, raising the possibility that Tim-1 may regulate CDS* T cell responses. We have developed several new antibodies, fusion proteins and transgenic and knock-out mice that will allow for the first time a detailed investigation of the role of Tim-3 in DCs, CNS microglia and CDS* Tc1 cells and Tim-1 in Th1, Th-17 and CDS* T cells. Using these tools, we propose to 1) Determine the function of Tim-3 in the innate immune system specifically on DCs and CNS derived microglial cells, 2) Define the role of Tim-3 in the generation and regulation of self-reactive CDS T cells, 3) Determine the role of Tim-1 signaling in the generation and effector function of encephalitogenic T cells including Th1, Th-17 and CDS* T cells. The studies proposed here will analyze the role of Tim-3 and Tim-1 in the regulation of autoimmune responses by affecting the function of DCs, CNS microglia, Th-1, Th-17, and CDS* T cells, the subsets of immune cells in which the functional role of Tim-1 and Tim-3 is not known.
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