title: Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo.
abstract: Patients surviving acute stages of sepsis often display impaired adaptive-immune responses. Using the cecal ligation and puncture model, we demonstrated that sepsis leads to substantial and long-lasting changes in the naive CD8 T cell repertoire, affecting the capacity of the host to respond to new infections. However, the identity of CD8 T cell-extrinsic factor(s) and mechanism(s) that contribute to impaired CD8 T cell responses after sepsis is unknown. Priming of naive CD8 T cells is critically dependent on the ability of dendritic cells (DCs) to provide Ag, costimulation, and inflammatory signal 3 cytokines; therefore, the sepsis-induced changes in the DC compartment might represent a contributing factor leading to diminished CD8 T cell immunity in septic hosts. In a direct test of this hypothesis, we show that, in addition to numerical decline, sepsis leads to functional impairments in DCs, diminishing their capacity to produce cytokines upon TLR stimulation in vitro or postinfection in vivo. Importantly, we demonstrated a direct link between DC dysfunction and impairments in CD8 T cell immunity after sepsis by directly targeting Ag to DCs. Finally, postsepsis Flt3 ligand treatment increased the number of DCs and improved DC function, including the ability to sense inflammation and produce IL-12, leading to improved primary CD8 T cell responses to newly encountered Ags. Thus, sepsis-induced numerical and functional loss of DCs contributes to the observed defects in CD8 T cell immunity, and therapeutic approaches designed to improve the status of the DC compartment after sepsis might facilitate the recovery of CD8 T cell immunity.
authors: Department of Pathology, University of Iowa, Iowa City, IA 52242.|Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
authors: Robert K
authors: 0000-0002-7290-2906
authors: RK
authors: Strother
authors: Department of Pathology, University of Iowa, Iowa City, IA 52242.|Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242.
authors: Derek B
authors: 0000-0002-3481-8797
authors: DB
authors: Danahy
authors: Microbiology, Immunology, and Cancer Biology Ph.D. Program, University of Minnesota, Minneapolis, MN 55455.|Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors: Dmitri I
authors: 0000-0001-7843-1503
authors: DI
authors: Kotov
authors: Department of Urology, University of Minnesota, Minneapolis, MN 55455.
authors: Tamara A
authors: TA
authors: Kucaba
authors: Department of Pathology, University of Iowa, Iowa City, IA 52242.|Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242.
authors: Zeb R
authors: 0000-0001-9157-3469
authors: ZR
authors: Zacharias
authors: Microbiology, Immunology, and Cancer Biology Ph.D. Program, University of Minnesota, Minneapolis, MN 55455.|Center for Immunology, University of Minnesota, Minneapolis, MN 55455.|Department of Urology, University of Minnesota, Minneapolis, MN 55455.|Minneapolis VA Health Care System, Minneapolis, MN 55417; and.
authors: Thomas S
authors: 0000-0002-7205-9859
authors: TS
authors: Griffith
authors: Department of Pathology, University of Iowa, Iowa City, IA 52242.|Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242.|Department of Microbiology, University of Iowa, Iowa City, IA 52242.
authors: Kevin L
authors: KL
authors: Legge
authors: Department of Pathology, University of Iowa, Iowa City, IA 52242; vladimir-badovinac@uiowa.edu.|Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242.
authors: Vladimir P
authors: 0000-0003-3180-2439
authors: VP
authors: Badovinac
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D000941:Antigens; D016207:Cytokines