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TRAIL Deficiency Does Not Rescue Impaired CD8⁺ T Cell Memory Generated in the Absence of CD4⁺ T Cell Help¹

Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195

Ag-specific CD8⁺ T cells immunized in the absence of CD4⁺ T cell help, so-called "unhelped" CD8⁺ T cells, are defective in function and survival. We investigated the role of the proapoptotic molecule TRAIL in this defect. We first demonstrate that TRAIL does not contribute to the CD8⁺ T cell response to Listeria monocytogenes strain expressing OVA (LmOVA) in the presence of CD4⁺ T cells. Secondly, we generated mice doubly deficient in CD4⁺ T cells and TRAIL and analyzed their CD8⁺ T cell response to LmOVA. Memory CD8⁺ T cells in double-deficient mice waned over time and were not protective against rechallenge, similar to their TRAIL-sufficient unhelped counterparts. To avoid the effects of CD4⁺ T cell deficiency during memory maintenance, and to address whether TRAIL plays a role in the early programming of the CD8⁺ T cell response, we performed experiments using heterologous prime and early boost immunizations. We did not observe activation-induced cell death of unhelped CD8⁺ T cells when mice were infected with followed vaccinia virus expressing OVA 9 days later by LmOVA infection. Furthermore, primary immunization of CD4⁺ T cell-deficient mice with cell-associated Ag followed by LmOVA infection did not reveal a role for TRAIL-mediated activation-induced cell death. Overall, our results suggest that CD4⁺ T cell help for the CD8⁺ T cell response is not contingent on the silencing of TRAIL expression and prevention of TRAIL-mediated apoptosis.

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 a grant from the National Institutes of Health (AI19335) and the Howard Hughes Medical Institute (to M.J.B.) and a Cancer Research Institute Predoctoral Training Grant in Tumor Immunology (to J.A.S.).

² Address correspondence and reprint requests to Dr. M. J. Bevan, Department of Immunology, Box 357370, Health Sciences Center, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195. E-mail address: mbevan{at}u.washington.edu

³ Abbreviations used in this paper: AICD, activation-induced cell death; B6, C57BL/6; Dbl KO, double knockout; ICS, intracellular cytokine staining; LCMV, lymphocytic choriomeningitis virus; LmOVA, Listeria monocytogenes strain expressing OVA; Vacc-OVA, recombinant vaccinia virus expressing OVA; WT, wild type.