Intrinsic Effects of Tim-3 on T cell exhaustion and TCR signaling

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): 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 na¿ve 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.