title: Differential impact of CD27 and 4-1BB costimulation on effector and memory CD8 T cell generation following peptide immunization.
abstract: The factors that determine differentiation of naive CD8 T cells into memory cells are not well understood. A greater understanding of how memory cells are generated will inform of ways to improve vaccination strategies. In this study, we analyzed the CD8 T cell response elicited by two experimental vaccines comprising a peptide/protein Ag and an agonist that delivers a costimulatory signal via CD27 or 4-1BB. Both agonists increased expansion of Ag-specific CD8 T cells compared with Ag alone. However, their capacity to stimulate differentiation into effector and memory cells differed. CD27 agonists promoted increased expression of perforin and the generation of short-lived memory cells, whereas stimulation with 4-1BB agonists favored generation of stable memory. The memory-promoting effects of 4-1BB were independent of CD4 T cells and were the result of programing within the first 2 d of priming. Consistent with this conclusion, CD27 and 4-1BB-stimulated CD8 T cells expressed disparate amounts of IL-2, IFN-γ, CD25, CD71, and Gp49b as early as 3 d after in vivo activation. In addition, memory CD8 T cells, generated through priming with CD27 agonists, proliferated more extensively than did 4-1BB-generated memory cells, but these cells failed to persist. These data demonstrate a previously unanticipated link between the rates of homeostatic proliferation and memory cell attrition. Our study highlights a role for these receptors in skewing CD8 T cell differentiation into effector and memory cells and provides an approach to optimize vaccines that elicit CD8 T cell responses.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Willoughby
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Kerr
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Rogel
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Taraban
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Buchan
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Johnson
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO16 6YD, United Kingdom aymen@soton.ac.uk.
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
mesh_terms: D000818:Animals; D000941:Antigens / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D007114:Immunization; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D011990:Receptors, Transferrin / Q000235:genetics / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists / Q000235:genetics / Q000276:immunology*
chemical_list: D000941:Antigens; D015703:Antigens, CD; C068126:CD71 antigen; D007376:Interleukin-2; C489448:Lilrb4 protein, mouse; D008562:Membrane Glycoproteins; D010455:Peptides; D011971:Receptors, Immunologic; D011990:Receptors, Transferrin; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma