title: Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals.
abstract: As a result of the growing burden of tumors and chronic infections, manipulating CD8 T cell responses for clinical use has become an important goal for immunologists. In this article, we show that dendritic cell (DC) immunization coupled with relatively early (days 1-3) or late (days 4-6) administration of enhanced IL-2 signals increase peak effector CD8 T cell numbers, but only early IL-2 signals enhance memory numbers. IL-2 signals delivered at relatively late time points drive terminal differentiation and marked Bim-mediated contraction and do not increase memory T cell numbers. In contrast, early IL-2 signals induce effector cell metabolic profiles that are more conducive to memory formation. Of note, downregulation of CD80 and CD86 was observed on DCs in vivo following early IL-2 treatment. Mechanistically, early IL-2 treatment enhanced CTLA-4 expression on regulatory T cells, and CTLA-4 blockade alongside IL-2 treatment in vivo prevented the decrease in CD80 and CD86, supporting a cell-extrinsic role for CTLA-4 in downregulating B7 ligand expression on DCs. Finally, DC immunization followed by early IL-2 treatment and anti-CTLA-4 blockade resulted in lower memory CD8 T cell numbers compared with the DC+early IL-2 treatment group. These data suggest that curtailed signaling through the B7-CD28 costimulatory axis during CD8 T cell activation limits terminal differentiation and preserves memory CD8 T cell formation; thus, it should be considered in future T cell-vaccination strategies.
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Marie T
authors.initials: MT
authors.lastname: Kim
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242; and.
authors.forename: Samarchith P
authors.initials: SP
authors.lastname: Kurup
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242;
authors.forename: Gabriel R
authors.identifier: 0000-0002-6681-1274
authors.initials: GR
authors.lastname: Starbeck-Miller
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; Department of Microbiology, University of Iowa, Iowa City, IA 52242; and Department of Pathology, University of Iowa, Iowa City, IA 52242 john-harty@uiowa.edu.
authors.forename: John T
authors.identifier: 0000-0001-7266-2802
authors.initials: JT
authors.lastname: Harty
mesh_terms: D000818:Animals; D060887:B7 Antigens / Q000235:genetics / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002452:Cell Count; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D007114:Immunization; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors
chemical_list: D060887:B7 Antigens; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007376:Interleukin-2