Accumulating evidence suggests that Thl that produce IFN-y and with specificity for myelin antigens are very potent in inducing the autoimmune disease of the CNS called experimental autoimmune encephalomyelitis (EAE). However, it has been difficult to differentiate autopathogenic Thl cells from other cells based on cell surface phenotype. Since Thl have been traditionally identified by the cytokines that they produce, it became important to identify cell surface molecules that can differentiate these cells. We have recently identified a novel gene family called TIM (T cell, Immunoglobulin and Mucin containing) that encodes cell surface molecules expressed on differentiated T cells. Whereas Tim-3 is expressed on the surface of differentiated Thl cells, our preliminary data suggests that another family member Tim-2 is expressed on Th2 cells. In addition, we have recently discovered an alternatively spliced, soluble form of Tim-3. The kinetics of expression of the soluble Tim-3 molecule during Thl differentiation is not known and its biological function has never been studied. We hypothesize that the function of Tim molecules may be to regulate expansion and effector functions of effector Th cells. This is supported by the observations that soluble fusion protein of Tim-3 (Tim-3Ig) was found to abrogate development of high dose tolerance and enhance Thl responses and EAE. In contrast, Tim2Ig fusion protein was found to inhibit development of EAE. The mechanism by which Tim-3Ig abrogate tolerance and enhance EAE and Tim2Ig fusion proteins protect mice from developing EAE is not understood. In this grant we propose to a) study the kinetics of expression of soluble Tim-3 and nature of cytokines and transcription factors that regulate expression of Tim2 and Tim3 on the T cell surface;b) study the kinetics of expression of Tim-2 protein on the surface of Th2 cells and determine the mechanism by which Tim2Ig inhibits development of EAE;and c) analyze whether Tim-3Ig fusion will also abrogate oral tolerance like the high dose tolerance and define the cellular mechanisms by which Tim-3Ig inhibits tolerance induction. These studies will provide fundamental information on the cellular and molecular mechanisms by which IFN-y and Thl cells play a role in the induction of EAE. Furthermore, these studies will define how the Tim family of molecules particularly Tim-2 and Tim-3 may be involved in the effector functions of the pathogenic autoreactive T cell responses and how blocking Tim pathway in vivo may alter the course of the CNS autoimmune disease, EAE.
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