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The Adaptor Molecule MyD88 Directly Promotes CD8 T Cell Responses to Vaccinia Virus¹

La Jolla Institute for Allergy and Immunology, Division of Molecular Immunology, La Jolla, CA 92037

Vaccinia virus (VACV) elicits a robust CD8 T cell response that plays an important role in host resistance. To date, there is little information on the molecules that are essential to generate large pools of VACV-specific effector CD8 T cells. In this study, we show that the adaptor molecule MyD88 is critical for the magnitude of primary CD8 T cell responses to both dominant and subdominant VACV epitopes. MyD88^–/– mice exhibit profound reduction in CD8 T cell expansion and antiviral cytokine production. Surprisingly, the defect was not due to impaired APC function, as MyD88^–/– dendritic cells matured normally and were able to promote strong CD8 T cell priming following VACV infection. Rather, adoptive transfer experiments demonstrated that intrinsic MyD88-dependent pathways in CD8 T cells were critical. MyD88-deficient CD8 T cells failed to accumulate in wild-type hosts and poor expansion of MyD88-deficient VACV-specific CD8 T cells resulted after virus infection. In contrast, no defect was evident in the absence of TRIF, TLR2, TLR4, TLR9, and IL-1R. Together, our results highlight an important role for MyD88 in initial antiviral CD8 T cell responses and suggest that targeting this pathway may be useful in promoting and sustaining anti-VACV immunity.

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 National Institutes of Health Grants AI77079 to S.S.-A., AI67341 to M.C., and AI33068, AI048073, and AI057840 to C.F.W. This is publication no. 1064 from the La Jolla Institute for Allergy and Immunology.

² Address correspondence and reprint requests to Dr. S. Salek-Ardakani, La Jolla Institute for Allergy and Immunology, Division of Molecular Immunology, 9420 Athena Circle, La Jolla, San Diego, CA 92037. E-mail address: ssalek{at}liai.org

³ Abbreviations used in this paper: VACV, vaccinia virus; DC, dendritic cell; LCMV, lymphocytic choriomeningitis virus; TRIF, Toll-IL-1R domain-containing adaptor-reducing IFN-β; WT, wild type.