IRF-8 regulates expansion of myeloid-derived suppressor cells and Foxp3+regulatory T cells and modulates Th2 immune responses to gastrointestinal nematode infection

Rajesh M. Valanparambil, Mifong Tam, Pierre Paul Gros, Jean Philippe Auger, Mariela Segura, Philippe Gros, Armando Jardim, Timothy G. Geary, Keiko Ozato, Mary M. Stevenson*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Citations (Scopus)
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Abstract

Interferon regulatory factor-8 (IRF-8) is critical for Th1 cell differentiation and negatively regulates myeloid cell development including myeloid-derived suppressor cells (MDSC). MDSC expand during infection with various pathogens including the gastrointestinal (GI) nematode Heligmosomoides polygyrus bakeri (Hpb). We investigated if IRF-8 contributes to Th2 immunity to Hpb infection. Irf8 expression was down-regulated in MDSC from Hpb-infected C57BL/6 (B6) mice. IRF-8 deficient Irf8-/-and BXH-2 mice had significantly higher adult worm burdens than B6 mice after primary or challenge Hpb infection. During primary infection, MDSC expanded to a significantly greater extent in mesenteric lymph nodes (MLN) and spleens of Irf8-/-and BXH-2 than B6 mice. CD4+GATA3+T cells numbers were comparable in MLN of infected B6 and IRF-8 deficient mice, but MLN cells from infected IRF-8 deficient mice secreted significantly less parasite-specific IL-4 ex vivo. The numbers of alternatively activated macrophages in MLN and serum levels of Hpb-specific IgG1 and IgE were also significantly less in infected Irf8-/-than B6 mice. The frequencies of antigen-experienced CD4+CD11ahiCD49dhicells that were CD44hiCD62L-were similar in MLN of infected Irf8-/-and B6 mice, but the proportions of CD4+GATA3+and CD4+IL-4+T cells were lower in infected Irf8-/-mice. CD11b+Gr1+cells from naïve or infected Irf8-/-mice suppressed CD4+T cell proliferation and parasite-specific IL-4 secretion in vitro albeit less efficiently than B6 mice. Surprisingly, there were significantly more CD4+T cells in infected Irf8-/-mice, with a higher frequency of CD4+CD25+Foxp3+T (Tregs) cells and significantly higher numbers of Tregs than B6 mice. In vivo depletion of MDSC and/or Tregs in Irf8-/-mice did not affect adult worm burdens, but Treg depletion resulted in higher egg production and enhanced parasite-specific IL-5, IL-13, and IL-6 secretion ex vivo. Our data thus provide a previously unrecognized role for IRF-8 in Th2 immunity to a GI nematode.

Original languageEnglish
Article numbere1006647
JournalPLoS Pathogens
Volume13
Issue number10
DOIs
Publication statusPublished - 01 Oct 2017

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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