T cell exhaustion has been recognized in recent years as an important mechanism for limiting immune pathology, although it may be desirable to circumvent this mechanism in a targeted fashion, to help eliminate viral reservoirs or tumors. However, the signals that drive and maintain exhaustion in T cells are still not well understood. Several surface protein markers of exhausted T cells have now been identified, including the transmembrane proteins PD-1 and Tim-3, among other markers. Despite the extensive amount of correlative evidence linking Tim-3 expression to dysfunction of T cell activation during exhaustion, little is known about the mechanisms by which Tim-3 contributes to the development and/or maintenance of exhaustion. This has been challenging, in part due to the fact that Tim-3 is not expressed by nave T cells, but is only detected after multiple rounds of activation. There is therefore a need for new reagents and model systems that will allow for the more direct definition of Tim-3 function in primary T cells. Unlike PD-1 or many other negative regulators of T cell activity, Tim-3 contains no motifs for the recruitment of inhibitory phosphatases. Rather, our recent work suggests that Tim-3 expression actually increases signaling through pathways that are normally associated with positive outcomes, i.e. efficient TCR/CD3-mediated T cell activation, at least under acute conditions. Correlative data from other groups indicate that T cell exhaustion results from chronic antigenic stimulation that extends the effector phase of T cell activation, at the expense of T cell memory. We hypothesize that Tim-3 contributes to T cell exhaustion by initially enhancing TCR-signaling pathways, leading to sustained and dysregulated T cell activation. This hypothesis will be tested with two Specific Aims.
In Aim 1, a novel mouse strain will be developed, with inducible (and reversible) expression of Tim-3 in the T cell compartment.
In Aim 2, it will be determined whether enforced Tim-3 expression drives T cell exhaustion and/or TCR signaling. The latter experiments will take advantage of a recently described reporter mouse, in which antigen receptor derived signaling can be distinguished from other sources.
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.
|Ferris, Robert L; Lu, Binfeng; Kane, Lawrence P (2014) Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion. J Immunol 193:1525-30|