title: Dendritic cells during polymicrobial sepsis rapidly mature but fail to initiate a protective Th1-type immune response.
abstract: Polymicrobial sepsis is associated with immunosuppression caused by the predominance of anti-inflammatory mediators and profound loss of lymphocytes through apoptosis. Dendritic cells (DC) are potent antigen-presenting cells and play a key role in T cell activation. We tested the hypothesis that DC are involved in sepsis-mediated immunosuppression in a mouse cecal ligation and puncture (CLP) model, which resembles human polymicrobial sepsis. At different time-points after CLP, DC from the spleen and peripheral lymph nodes were characterized in terms of expression of costimulatory molecules, cytokine synthesis, and subset composition. Splenic DC strongly up-regulated CD86 and CD40 but not CD80 as soon as 8 h after CLP. In contrast, lymph node DC equally increased the expression of CD86, CD40, and CD80. However, this process of maturation occurred later in the lymph nodes than in the spleen. Splenic DC from septic mice were unable to secrete interleukin (IL)-12, even upon stimulation with CpG or lipopolysaccharide+CD40 ligand, but released high levels of IL-10 in comparison to DC from control mice. Neutralization of endogenous IL-10 could not restore IL-12 secretion by DC of septic mice. In addition, the splenic CD4+CD8- and CD4-CD8+ subpopulations were lost during sepsis, and the remaining DC showed a reduced capacity for allogeneic T cell activation associated with decreased IL-2 synthesis. Thus, during sepsis, splenic DC acquire a state of aberrant responsiveness to bacterial stimuli, and two DC subtypes are selectively lost. These changes in DC behavior might contribute to impaired host response against bacteria during sepsis.
authors.affiliation: Department of Trauma Surgery, University Hospital Essen, Virchowstr. 171, D-45147 Essen, Germany. stefanie.flohe@medizin.uni-essen.de
authors.forename: Stefanie B
authors.initials: SB
authors.lastname: Flohé
authors.forename: Hemant
authors.initials: H
authors.lastname: Agrawal
authors.forename: Daniel
authors.initials: D
authors.lastname: Schmitz
authors.forename: Michaela
authors.initials: M
authors.lastname: Gertz
authors.forename: Sascha
authors.initials: S
authors.lastname: Flohé
authors.forename: F Ulrich
authors.initials: FU
authors.lastname: Schade
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007108:Immune Tolerance / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000503:physiopathology; D018417:Th1 Cells / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D016753:Interleukin-10; D018664:Interleukin-12