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

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.