title: Memory CD8+ T cells require CD28 costimulation.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Annie B
authors.initials: AB
authors.lastname: Borowski
authors.forename: Alina C
authors.initials: AC
authors.lastname: Boesteanu
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Mueller
authors.forename: Caterina
authors.initials: C
authors.lastname: Carafides
authors.forename: David J
authors.initials: DJ
authors.lastname: Topham
authors.forename: John D
authors.initials: JD
authors.lastname: Altman
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Jennings
authors.forename: Peter D
authors.initials: PD
authors.lastname: Katsikis
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D005260:Female; D006678:HIV / Q000276:immunology; D006566:Herpesviridae Infections / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology*; D008459:Measles virus / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D019496:Cancer Vaccines; D019253:Proto-Oncogene Proteins c-bcl-2; D014765:Viral Vaccines