T helper type 2-polarized invariant natural killer T cells reduce disease severity in acute intra-abdominal sepsis

Clin Exp Immunol. 2014 Nov;178(2):292-309. doi: 10.1111/cei.12404.

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.

Keywords: Th2 response; acute intra-abdominal sepsis; glycolipids; invariant natural killer T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Glycolipids / administration & dosage
  • Glycolipids / pharmacology
  • Humans
  • Inflammation Mediators / metabolism
  • Lymphocyte Count
  • Male
  • Mice
  • Middle Aged
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Organ Specificity / immunology
  • Patient Outcome Assessment
  • Sepsis / drug therapy
  • Sepsis / immunology*
  • Sepsis / mortality
  • Sepsis / pathology*
  • Severity of Illness Index
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / immunology
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism

Substances

  • Cytokines
  • Glycolipids
  • Inflammation Mediators
  • tetracosanoic acid 1-galactopyranosyloxy-3,4-dihydroxydec-2-yl amide