IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection

Mucosal Immunol. 2016 Nov;9(6):1407-1417. doi: 10.1038/mi.2016.4. Epub 2016 Feb 17.

Abstract

Immunity to many human and murine gastrointestinal helminth parasites requires interleukin-4 (IL-4)-directed type 2 helper (TH2) differentiation of CD4+ T cells to elicit type-2 immunity. Despite a good understanding of the inflammatory cascade elicited following helminth infection, the initial source of IL-4 is unclear. Previous studies using the rat helminth parasite Nippostronglyus brasiliensis, identified an important role for basophil-derived IL-4 for TH2 differentiation. However, basophils are redundant for TH2 differentiation following infection with the natural helminth parasite of mice Heligmosomoides polygyrus, indicating that other sources of IL-4 are required. In this study using H. polygyrus, which is controlled by IL-4-dependent immunity, we identified that group-2 innate lymphoid cells (ILC2s) produced significant amounts of IL-4 and IL-2 following H. polygyrus infection. Leukotriene D4 was sufficient to stimulate IL-4 secretion by ILC2s, and the supernatant from activated ILC2s could potently drive TH2 differentiation in vitro in an IL-4-dependent manner. Furthermore, specific deletion of IL-4 from ILC2s compromised TH2 differentiation in vivo. Overall, this study highlights a previously unrecognized and important role for ILC2-derived IL-4 for TH2 differentiation in a natural TH2-dependent model of human helminthiasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / immunology*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Host-Parasite Interactions / immunology
  • Immunity, Innate*
  • Interleukin-4 / biosynthesis*
  • Lymph Nodes / immunology
  • Lymphocyte Subsets / immunology*
  • Lymphocyte Subsets / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Nematospiroides dubius / immunology*
  • Strongylida Infections / immunology
  • Strongylida Infections / metabolism
  • Th2 Cells / cytology*
  • Th2 Cells / immunology
  • Th2 Cells / metabolism

Substances

  • Cytokines
  • Interleukin-4