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TNFR2-Deficient Memory CD8 T Cells Provide Superior Protection against Tumor Cell Growth¹

Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

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-7R). 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Canadian Cancer Society (Grant No. 019458 to H.-S.T).

² Current address: Toronto Medical Discovery Tower, Medical and Related Sciences Centre, University Health Network, Toronto, ON, Canada. E-mail address: edward.kim{at}uhnresearch.ca

³ E.Y.K. and S.-J.T. are co-first authors.

⁴ Address correspondence and reprint requests to Dr. Hung-Sia Teh, Department of Microbiology and Immunology, Life Sciences Centre, University of British Columbia, Room 3509, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada. E-mail address: teh{at}interchange.ubc.ca

⁵ Abbreviations used in this paper: TNFR, TNF receptor; AICD, activation induced cell death; WT, wild type; 7-AAD, 7-aminoactinomycin D; rLM-OVA, recombinant LM that expressing OVA; CFU, colony forming unit; E.G7, recombinant EL4 tumor cells expressing ovalbumin; LM, Listeria monocytogenes; TRP2, tyrosinase-related protein-2.