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.
The immune system has evolved to protect individuals from dangerous pathogens, like viruses and bacteria, and can also eliminate some tumors, before they become life threatening. However, an overly vigorous immune response can cause damage to sensitive tissues. Thus, in some cases where the pathogen (or tumor) is not efficiently cleared, there exist mechanisms to impair further activity of that particular immune response. While this may spare the host from immune-mediated damage, it can also allow certain viruses (like HIV) to establish reservoirs in the body; it may also allow tumors to ?escape? further interference from the immune system. The studies proposed in this application will deepen our knowledge of this phenomenon, sometimes called ?immune exhaustion,? by defining the role of a specific protein known as Tim-3, which has recently been implicated in this process.