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* Department of Immunology and
Washington National Primate Center, University of Washington School of Medicine, Seattle, WA 98195
Understanding the factors contributing to the generation of immune memory is important for rational vaccine design. In this study, we addressed the individual and combined roles of Ag and inflammation in sustaining the ability of primed CD8 T cells to clonally expand and differentiate into memory cells. We transferred CD8 T cells that were primed for a brief period into naive mice, mice infected with a pathogen not carrying the specific Ag (inflammation only), mice infected with a pathogen carrying the donor cell-specific Ag (inflammation plus Ag), or into mice exposed to soluble Ag (Ag only). We found that the donor CD8 T cells continued to proliferate in all the four conditions, but their ability to clonally expand and differentiate into memory cells was 
1000-fold higher when transferred into mice acutely infected with pathogen carrying the relevant Ag. Memory cells generated under conditions of sustained exposure to inflammation and Ag during the priming phase were superior in their ability to elicit recall responses on a per cell basis. Thus, simultaneous and sustained exposure of donor CD8 T cells to inflammatory and antigenic stimuli, following the initial priming phase, leads to the greatest expansion of CD8 T cells at the peak of the immune response and induces an optimal memory differentiation program. These results suggest that vaccination strategies should attempt to provide sustained exposure to Ag plus inflammation but not either alone following the initial priming.
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 in part by National Institutes of Health Grants 1R01AI053146 and R21AI051386 (to K.M.-K.) and by funds from the Washington National Primate Center and the University of Washington Department of Immunology. A.S. is supported by a National Cancer Institute training grant.
2 Address correspondence and reprint requests to Dr. Kaja Murali-Krishna, Department of Immunology and Washington National Primate Center, Box 357650 Health Sciences Building, 1959 Northeast Pacific Street, Seattle, WA 98195. E-mail address: mkaja{at}u.washington.edu
3 Abbreviations used in this paper: WT, wild type; rLM-OVA, recombinant Listeria monocytogenes expressing OVA; LCMV, lymphocytic choriomeningitis virus; rVSV-OVA, recombinant vesicular stomatitis virus expressing OVA; Lm, Listeria monocytogenes; DC, dendritic cell; Tg, transgenic.
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