OR.107. TIM-1 Plays a Crucial Role in the Expansion of Autopathogneic T-Cells and Regulation of Autoimmunity [abstract only]

T-cell immunoglobulin and mucin (TIM) family Members are differentially expressed on Th1 and Th2 cells. Polymorphisms of TIM-1 have been associated with susceptibility to asthma; however, its role in regulating autoimmunity has not been studied. Here, we have used an agonistic antiTIM-1 antibody (Ab, Clone 3B3) which has previously been shown to costimulate T-cell activation and expansion, to analyze the role of TIM-1 in the development and regulation of experimental autoimmune encephalomyelitis (EAE). Treatment with 3B3 dramatically enhances the severity of EAE as well as the frequency of encephalitogenic CD4+ T-cells and the production of IFN-g and IL-17 by these cells. Furthermore, administration of 3B3 breaks self-tolerance and induces EAE in the disease resistant B10.S strain. We have utilized another anti-TIM-1 Ab (RMT1-10) that does not costimulate T-cell activation in vitro. In contrast to 3B3, treatment with RMT1-10 inhibits the development of EAE and reduces the frequency of encephalitogenic CD4+ T-cells with a commensurate decrease in the production of IFN-g and IL-17. Treatment with RMT1-10 causes CD4+ T-cells to produce more IL-4 and IL-10. We provide evidence that both 3B3 and RMT1-10 bind to the same epitope in the Ig domain of TIM-1, but the binding affinity of 3B3 is much higher than that of RMT1-10. These data suggest that TIM-1 engagement with the agonistic Ab, along with TcR ligation, costimulates T-cell expansion with pro-inflammatory IFN-g and IL-17 production resulting in the breakdown of self-tolerance and development of autoimmunity, whereas blocking anti-TIM-1 Ab causes a decrease in the autopathogenic Th1/ThIL-17 responses. This study demonstrates that TIM-1 is a key cell surface molecule that regulates effector T-cell response and depending on hopw the molecule is engaged, autoimmune responses can be either enhanced or inhibited in vivo

Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function

It has been suggested that T cell immunoglobulin mucin (Tim)-1 expressed on T cells serves to positively costimulate T cell responses. However, crosslinking of Tim-1 by its ligand Tim-4 resulted in either activation or inhibition of T cell responses, thus raising the issue of whether Tim-1 can have a dual function as a costimulator. To resolve this issue, we tested a series of monoclonal antibodies specific for Tim-1 and identified two antibodies that showed opposite functional effects. One anti–Tim-1 antibody increased the frequency of antigen-specific T cells, the production of the proinflammatory cytokines IFN-γ and IL-17, and the severity of experimental autoimmune encephalomyelitis. In contrast, another anti–Tim-1 antibody inhibited the generation of antigen-specific T cells, production of IFN-γ and IL-17, and development of autoimmunity, and it caused a strong Th2 response. Both antibodies bound to closely related epitopes in the IgV domain of the Tim-1 molecule, but the activating antibody had an avidity for Tim-1 that was 17 times higher than the inhibitory antibody. Although both anti–Tim-1 antibodies induced CD3 capping, only the activating antibody caused strong cytoskeletal reorganization and motility. These data indicate that Tim-1 regulates T cell responses and that Tim-1 engagement can alter T cell function depending on the affinity/avidity with which it is engaged