Concerted IL-25R and IL-4Rα signaling drive innate type 2 effector immunity for optimal helminth expulsion

Elife. 2018 Sep 21:7:e38269. doi: 10.7554/eLife.38269.

Abstract

Interleukin 25 (IL-25) is a major 'alarmin' cytokine, capable of initiating and amplifying the type immune response to helminth parasites. However, its role in the later effector phase of clearing chronic infection remains unclear. The helminth Heligmosomoides polygyrus establishes long-term infections in susceptible C57BL/6 mice, but is slowly expelled in BALB/c mice from day 14 onwards. We noted that IL-25R (Il17rb)-deficient BALB/c mice were unable to expel parasites despite type 2 immune activation comparable to the wild-type. We then established that in C57BL/6 mice, IL-25 adminstered late in infection (days 14-17) drove immunity. Moreover, when IL-25 and IL-4 were delivered to Rag1-deficient mice, the combination resulted in near complete expulsion of the parasite, even following administration of an anti-CD90 antibody to deplete innate lymphoid cells (ILCs). Hence, effective anti-helminth immunity during chronic infection requires an innate effector cell population that is synergistically activated by the combination of IL-4Rα and IL-25R signaling.

Keywords: cytokines; heligmosomoides polygyrus; immunology; infectious disease; inflammation; microbiology; mouse; myeloid cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Host-Parasite Interactions / immunology
  • Immunity, Innate / drug effects
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Interleukin-17 / immunology
  • Interleukin-17 / pharmacology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nematospiroides dubius / immunology*
  • Nematospiroides dubius / physiology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Receptors, Cell Surface / metabolism
  • Receptors, Interleukin-17 / genetics
  • Receptors, Interleukin-17 / immunology*
  • Receptors, Interleukin-17 / metabolism
  • Strongylida Infections / genetics
  • Strongylida Infections / immunology*
  • Strongylida Infections / parasitology
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism

Substances

  • Il17rb protein, mouse
  • Il4ra protein, mouse
  • Interleukin-17
  • Receptors, Cell Surface
  • Receptors, Interleukin-17