TNFR2-Deficient Memory CD8 T Cells Provide Superior Protection against Tumor Cell Growth

Abstract

TNF receptor-2 (TNFR2) plays a critical role in promoting the activation and survival of naive T cells during the primary response. Interestingly, anti-CD3 plus IL-2 activated TNFR2−/− CD8 T cells are highly resistant to activation-induced cell death (AICD), which correlates with high expression levels of prosurvival molecules such as Bcl-2, survivin, and CD127 (IL-7Rα). We determined whether the resistance of activated TNFR2−/− CD8 T cells to AICD contributes to more effective protection against tumor cell growth. We found that during a primary tumor challenge, despite initial inferiority in controlling tumor cell growth, TNFR2−/− mice were able to more effectively control tumor burden over time compared with wild-type (WT) mice. Furthermore, vaccination of TNFR2−/− mice with recombinant Listeria monocytogenes that express OVA confers better protection against the growth of OVA-expressing E.G7 tumor cells relative to similarly vaccinated WT mice. The enhanced protection against tumor cell growth was not due to more effective activation of OVA-specific memory CD8 T cells in vaccinated TNFR2−/− mice. In vitro studies indicate that optimally activated OVA-specific TNFR2−/− CD8 T cells proliferated to the same extent and possess similar cytotoxicity against E.G7 tumor cells as WT CD8 T cells. However, relative to WT cells, activated OVA-specific TNFR2−/− CD8 T cells were highly resistant to AICD. Thus, the enhanced protection against E.G7 in TNFR2−/− mice is likely due to the recruitment and activation of OVA-specific memory TNFR2−/− CD8 T cells and their prolonged survival at the tumor site.

CD8+ T Cells That Coexpress RORγt and T-bet Are Functionally Impaired and Expand in Patients with Distal Bile Duct Cancer

“…In humans, expression of CTLA-4, PD-1, LAG-3, and Tim-3 in CD8 + T cells marks their activation and differentiation status (32), and it is also associated with exhaustion (33) (Fig. 4D) (35,36). We found that the purified CD8 + T cells from DBDC patients to a high degree underwent apoptosis in vitro in the absence of TCR and costimulation (Fig.…”

Tumor Necrosis Factor Receptor 2 Restricts the Pathogenicity of CD8+ T Cells in Mice With Colitis

“…CD8 + T cells in Il10 −/− Tnfr2 −/− colons expressed significantly elevated levels of TNF (Fig 4D), whereas other immune cell subsets expressed equivalent levels of TNF (data not shown). TNF is increased during CD8+ T cell activation 29 , and TNF-TNFR2 signaling mediates activation-induced cell death in CD8+ T cells as part of a negative feedback mechanism 16,30,31 . This suggested that the increase in CD8+ T cells in the absence of TNFR2 occurred because these cells were resistant to activation-induced cell death.…”

Shedding of TNF receptor 2 by effector CD8+ T cells by ADAM17 is important for regulating TNF-α availability during influenza infection

“…TNFR2 2/2 initially impairs T cell proliferation and survival, a result of, in part, reduced expression of IL-2 [9,10]. This early defect in survival can be overcome with the addition of exogenous IL-2, and after becoming effector cells, TNFR2 2/2 CD8 + T cells are highly resistant to activation-induced cell death [7,11]. These studies suggest that TNFR2 expression has an important role in CD8 + T cell activation and turnover.…”