Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes

J Exp Med. 2011 Mar 14;208(3):593-604. doi: 10.1084/jem.20100793. Epub 2011 Feb 28.

Abstract

The innate signaling pathways for Th2 immunity activated by inhaled antigens are not well defined. We previously identified Dectin-2 as a receptor for glycans in allergen extracts from the house dust mite Dermatophagoides farinae (Df) that mediates cysteinyl leukotriene (cys-LT) generation from pulmonary CD11c+ cells and from GM-CSF-cultured bone marrow cells (BMCs(GM-CSF)). Using lentiviral knockdown of Dectin-2 in BMCs(GM-CSF) and adoptive transfer of Df-pulsed BMCs(GM-CSF) to sensitize naive mice, we now report that Dectin-2 is critical for the development of Df-elicited eosinophilic and neutrophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Sensitization with Df-pulsed BMCs(GM-CSF) from LTC(4) synthase (LTC(4)S)-deficient mice or type 1 cys-LT receptor (CysLT1R)-deficient mice demonstrated that both proteins were required for Df-elicited eosinophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Direct sensitization and challenge of Ltc4s-/- and Cysltr1-/- mice confirmed that cys-LTs mediate these parameters of Df-elicited Th2 pulmonary inflammation. Thus, the Dectin-2-cys-LT pathway is critical for the induction of Th2 immunity to a major allergen, in part through CysLT1R. These findings identify a previously unrecognized link between a myeloid C-type lectin receptor and Th2 immunity.

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / physiology
  • Cysteine / biosynthesis
  • Cysteine / physiology*
  • Eosinophils / immunology
  • Eosinophils / physiology
  • Inflammation / immunology
  • Inflammation / physiopathology
  • Interleukin-10 / biosynthesis
  • Interleukin-10 / physiology
  • Interleukin-23 / biosynthesis
  • Interleukin-23 / physiology
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / physiology
  • Lectins, C-Type / immunology*
  • Leukotrienes / biosynthesis
  • Leukotrienes / physiology*
  • Lung / immunology
  • Lung / physiopathology
  • Lymph Nodes / immunology
  • Lymph Nodes / physiopathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Receptors, Leukotriene / physiology
  • Th2 Cells / immunology*
  • Th2 Cells / physiology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Interleukin-23
  • Interleukin-6
  • Lectins, C-Type
  • Leukotrienes
  • Receptors, Leukotriene
  • Tumor Necrosis Factor-alpha
  • cysteinyl-leukotriene
  • dectin-2, mouse
  • Interleukin-10
  • Cysteine