The Foxp3+ regulatory T-cell population requires IL-4Rα signaling to control inflammation during helminth infections

PLoS Biol. 2018 Oct 31;16(10):e2005850. doi: 10.1371/journal.pbio.2005850. eCollection 2018 Oct.

Abstract

Forkhead box P3 (Foxp3+) regulatory T (Treg)-cell function is controlled by environmental cues of which cytokine-mediated signaling is a dominant component. In vivo, interleukin-4 (IL-4)-mediated signaling via IL-4 receptor alpha (IL-4Rα) mediates Treg cell transdifferentiation into ex-Foxp3 T helper 2 (Th2) or T helper 17 (Th17) cells. However, IL-4-mediated signaling also reinforces the Foxp3 Treg compartment in vitro. We generated Foxp3-specific IL-4Rα-deficient mice and demonstrated differential efficiency of IL-4Rα deletion in male (approximately 90%) and female (approximately 40%) animals, because of cyclic recombinase (Cre)-mediated X-linked foxp3 inactivation. Irrespective of the degree of IL-4Rα deletion within the Foxp3+ Treg cell population, mice showed exacerbation of immune effector responses with aggravated tissue pathology in tissue-dwelling helminth infections (Schistosoma mansoni or Nippostrongylus brasiliensis). Mechanistically, IL-4Rα deletion in males and females led to a reduced expression of Foxp3 and subsequently an impaired accumulation of Foxp3+ Treg cells to inflamed tissues. In-depth cellular typing by flow cytometry revealed that the impairment of IL-4Rα-mediated signaling during helminth infections decreased the ability of central Treg cells to convert into effector Treg (eTreg) cells and caused a significant down-regulation of markers associated with Treg cell migration (C-X-C motif chemokine receptor 3 [CXCR3]) and accumulation in inflamed tissues (GATA binding protein 3 [GATA3]) as well as survival (B cell lymphoma 2 [Bcl-2]). These findings unprecedentedly, to our knowledge, uncover a role for IL-4Rα signaling in the positive regulation of Foxp3+ Treg cell function in vivo. Complementing our past knowledge on a widely reported role for IL-4Rα signaling in the negative regulation and transdifferentiation of Foxp3+ Treg cells in vivo, our present findings reveal the host requirement for an intact, but not reduced or potentiated, IL-4Rα-mediated signaling on Foxp3+ Treg cells to optimally control inflammation during helminth infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Forkhead Transcription Factors / metabolism
  • Forkhead Transcription Factors / physiology*
  • Helminthiasis / immunology*
  • Helminthiasis, Animal / immunology
  • Helminths / pathogenicity
  • Inflammation / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Nippostrongylus
  • Receptors, Cell Surface / physiology*
  • Schistosoma mansoni
  • Schistosomiasis mansoni / immunology
  • Schistosomiasis mansoni / veterinary
  • Signal Transduction
  • Strongylida Infections
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / physiology
  • Th17 Cells
  • Th2 Cells

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Il4ra protein, mouse
  • Receptors, Cell Surface