Year: 2013
Type: dissertation
Abstract: 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-kappaB pathway. I extended these findings to show that TRAF1 was also required, as well as either cIAP1 or cIAP2, to activate the canonical NF-kappaB pathway. I also showed that 4-1BB is capable of inducing TRAF3 degradation to induce activation of the non-canonical NF-kappaB pathway. T cells activated in the absence of costimulation do not show activation of the non-canonical NF-kappaB pathway. However, I showed that loss of TRAF1 or cIAP1 results in the unrestrained activation of the non-canonical NF-kappaB 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 TRAF2 expression. This suggests a mechanism of limiting 4-1BB costimulation only to activated T cells that are responding under optimal conditions. I conclude with a current model of the signaling that occurs downstream of 4-1BB to induce its biological effects on T cells.
Source: TSpace (University of Toronto)
Author: Ann J. McPherson
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2409056308