Journal article
Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo
The Journal of immunology (1950), Vol.197(11), pp.4301-4311
12/01/2016
DOI: 10.4049/jimmunol.1601463
PMCID: PMC5123856
PMID: 27798171
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.
Details
- Title: Subtitle
- Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo
- Creators
- Robert K Strother - Carver College of Medicine, University of Iowa, Iowa City, IA 52242Derek B Danahy - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242Dmitri I Kotov - Center for Immunology, University of Minnesota, Minneapolis, MN 55455Tamara A Kucaba - Department of Urology, University of Minnesota, Minneapolis, MN 55455Zeb R Zacharias - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242Thomas S Griffith - Minneapolis VA Health Care System, Minneapolis, MN 55417; andKevin L Legge - Department of Microbiology, University of Iowa, Iowa City, IA 52242Vladimir P Badovinac - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.197(11), pp.4301-4311
- DOI
- 10.4049/jimmunol.1601463
- PMID
- 27798171
- PMCID
- PMC5123856
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Publisher
- United States
- Grant note
- I01 BX001324 / BLRD VA R01 AI114543 / NIAID NIH HHS R21 AI119160 / NIAID NIH HHS T35 HL007485 / NHLBI NIH HHS R01 AI083286 / NIAID NIH HHS R01 GM113961 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS T32 AI007313 / NIAID NIH HHS R01 GM115462 / NIGMS NIH HHS
- Language
- English
- Date published
- 12/01/2016
- Academic Unit
- Microbiology and Immunology; Pathology
- Record Identifier
- 9984047657502771
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