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The Role of TRAF1 in Signaling Downstream of 4-1BB on CD8 T Cells

4-1BB is a T cell costimulatory member of the TNFR superfamily known to regulate T cell responses. Engagement of 4-1BB contributes to T cell proliferation, cytokine production, and cell survival. Elucidating how 4-1BB induces these responses in T cells is crucial for understanding how these responses can be manipulated for immunotherapy. Upon engagement with its ligand, 4-1BB recruits TRAF1 and TRAF2 to its intracellular domain to induce downstream signaling pathways that influence the T cell’s biology. 4-1BB had previously been shown to require TRAF2 to activate the canonical NF-B pathway. I extended these findings to show that TRAF1 was also required, as well as either cIAP1 or cIAP2, to activate the canonical NF-B pathway. I also showed that 4-1BB is capable of inducing TRAF3 degradation to induce activation of the non-canonical NF-B pathway. T cells activated in the absence of costimulation do not show activation of the non-canonical NF-B pathway. However, I showed that loss of TRAF1 or cIAP1 results in the unrestrained activation of the non-canonical NF-B pathway, even in the absence of costimulation, resulting in hyperproliferation and excess cytokine production that normally requires costimulation. I also showed that TRAF1 expression was required in activated T cells during 4-1BB signaling in nutrient stressed T cells to stabilize