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* Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129;
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642; and
Emory Vaccine Research Center, Atlanta, GA 30329
CD8+ T cells are a critical component of the adaptive immune response against infections and tumors. A current paradigm in immunology is that naive CD8+ T cells require CD28 costimulation, whereas memory CD8+ T cells do not. We show here, however, that during viral infections of mice, costimulation is required in vivo for the reactivation of memory CD8+ T cells. In the absence of CD28 costimulation, secondary CD8+ T cell responses are greatly reduced and this impairs viral clearance. The failure of CD8+ T cells to expand in the absence of CD28 costimulation is CD4+ T cell help independent and is accompanied by a failure to down-regulate Bcl-2 and by cell cycle arrest. This requirement for CD28 costimulation was shown in both influenza A and HSV infections. Thus, contrary to current dogma, memory CD8+ T cells require CD28 costimulation to generate maximal secondary responses against pathogens. Importantly, this CD28 requirement was shown in the context of real infections were multiple other cytokines and costimulators may be up-regulated. Our findings have important implications for pathogens, such as HIV and measles virus, and tumors that evade the immune response by failing to provide CD28 costimulation. These findings also raise questions about the efficacy of CD8+ T cell-based vaccines against such pathogens and tumors.
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 study was supported by Grants R01 AI66215, R01 AI46719, and R01 AI62437 from the National Institutes of Health (to P.D.K.).
2 Address correspondence and reprint requests to Dr. Peter D. Katsikis, Department of Microbiology and Immunology and Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129. E-mail address: Peter.Katsikis{at}DrexelMed.edu
3 Abbreviations used in this paper: DC, dendritic cell; NP, nuclear protein; MLN, mediastinal lymph node.
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