Regulation of T cell activation and exhaustion by Tim-3

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Abstract The transmembrane protein Tim-3 is expressed on a subset of activated T cells, and is particularly enriched on so-called exhausted T cells, which are associated with chronic viral infection and the tumor microenvironment. As such, Tim-3 is being actively explored as a potential target for tumor immunotherapy. However, significant questions remain about how Tim-3 expression is regulated during acute vs. chronic infection, and how signaling pathways downstream of Tim-3 modulate T cell function. Using LCMV infection, we have found that Tim-3 expression and signaling augment early T cell activation during both primary and recall responses, but that Tim-3 is dispensable for the development of T cell exhaustion. Furthermore, we have found that the transcription factor Blimp1 can control Tim-3 expression under some, but not all, circumstances. Here we will further define the effects of Tim-3 on sculpting the overall CD4+ and CD8+ T cell responses to specific viral epitopes of LCMV. We will also define the specific requirements for Blimp1 and downstream factors, including the E-box binding factor inhibitor Id3. Finally, we will determine the role of signaling through the cytoplasmic tail of Tim-3 in regulating T cell activation, memory and exhaustion.