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

Grant support

International Centre for Genetic Engineering and Biotechnology http://www.icgeb.org/home.html to FB. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The National Research Foundation (NRF) of South Africa and the Department of Science and Technology (DST), and the South African Research Chair Initiative http://www.nrf.ac.za/ (grant number 443277) to FB. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The South African Medical Research Council (SAMRC) www.mrc.ac.za/ (grant number 415598) to FB. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The International Centre for Genetic Engineering and Biotechnology (ICGEB) icgeb.org. PhD Fellowship to NAA. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Academy of Science of South Africa https://www.assaf.org.za/. Sydney Brenner Fellowship to JKN. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.