title: T helper type 2-polarized invariant natural killer T cells reduce disease severity in acute intra-abdominal sepsis.
abstract: Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNK T) cells are potent regulatory lymphocytes that can produce pro- and/or anti-inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of iNK T cells in their peripheral blood (as a percentage of their circulating T cells) compared to non-septic patients. We therefore investigated the role of iNK T cells in a mouse model of intra-abdominal sepsis (IAS). Our data show that iNK T cells are pathogenic in IAS, and that T helper type 2 (Th2) polarization of iNK T cells using the synthetic glycolipid OCH significantly reduces mortality from IAS. This reduction in mortality is associated with the systemic elevation of the anti-inflammatory cytokine interleukin (IL)-13 and reduction of several proinflammatory cytokines within the spleen, notably interleukin (IL)-17. Finally, we show that treatment of sepsis with OCH in mice is accompanied by significantly reduced apoptosis of splenic T and B lymphocytes and macrophages, but not natural killer cells. We propose that modulation of iNK T cell responses towards a Th2 phenotype may be an effective therapeutic strategy in early sepsis.
authors: Division of General Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
authors: R V
authors: RV
authors: Anantha
authors: D M
authors: DM
authors: Mazzuca
authors: S X
authors: SX
authors: Xu
authors: S A
authors: SA
authors: Porcelli
authors: D D
authors: DD
authors: Fraser
authors: C M
authors: CM
authors: Martin
authors: I
authors: I
authors: Welch
authors: T
authors: T
authors: Mele
authors: S M M
authors: SM
authors: Haeryfar
authors: J K
authors: JK
authors: McCormick
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006017:Glycolipids / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D009928:Organ Specificity / Q000276:immunology; D063868:Patient Outcome Assessment; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D012720:Severity of Illness Index; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D006017:Glycolipids; D018836:Inflammation Mediators; C501055:tetracosanoic acid 1-galactopyranosyloxy-3,4-dihydroxydec-2-yl amide
keywords: Th2 response; acute intra-abdominal sepsis; glycolipids; invariant natural killer T cells