T cells are pivotal players in the adaptive immune response. However, when continuously exposed to antigen, as in persistent infection or cancer, T cells lose effector function and ultimately become exhausted, leading to chronic infection or progressive disease. Recent therapeutic advances are based on reversing these natural mechanisms set in place to “quiet” activated T cells during the resolution phase of an immune response, and in doing so, reinvigorate immune responses crippled by T cell exhaustion. However, response rates remain low in many settings; thus, additional strategies are needed. Crucial for developing such strategies is to identify new targetable pathways, which is currently hampered by our limited basic knowledge of the negative regulatory pathways that inhibit T cell activation. We recently discovered that the pseudokinase Trib1 is a novel negative regulator of T cell activation, which is induced upon T cell receptor (TCR) stimulation. Our overall goal is to determine the cellular and molecular mechanisms by which Trib1 regulates T cell responses. Our preliminary data generated both in vitro and in vivo suggest that in the absence of Trib1, T cells are hyper-activated and are better able to control chronic infections. Mechanistically, Trib1 appears to exert its effects on T cells via a novel mechanism of regulating NF-κB. Based on these preliminary data, our overarching hypothesis is that Trib1 suppresses signaling pathways that promote T cell activation and promotes immune cell exhaustion by limiting T cell effector function and B cell help. This hypothesis will be tested in two aims: Aim 1 will define the cellular responses regulated by Trib1, and Aim 2 will determine the signaling pathways responsible for these findings. Our findings may lead to new insights into controlling T cell activation and exhaustion in multiple scenarios, including chronic infections and cancer, and in doing so, identify new avenues for therapeutic interventions.

Project Narrative We recently discovered an important function for Tribbles, a protein best known for its role as an adapter in protein degradation, in T cell function. Our research will provide key insights into how Tribbles regulates T cell activation and exhaustion, and in doing so, may reveal new opportunities for therapeutic targeting.