IL-12p40 and Type 1 immunity are induced by Toxoplasma gondii in the absence of the TLR-MyD88 signaling cascade

Abstract

Abstract Toxoplasma gondii is an orally acquired pathogen that induces strong, protective IFN-γ based immunity. The response in mice is driven in part by well-characterized MyD88-dependent signaling pathways. The objective of this study was to determine the induction of immune responses that do not involve this Toll-like receptor (TLR)/IL-1 family receptor adaptor molecule, with particular focus on events in the intestinal mucosa. Using eYFP-IL-12p40 reporter mice on an MyD88−/− background, we identified dendritic cells, macrophages, and neutrophils as cellular sources of MyD88-independent IL-12 after peroral T. gondii infection. While infection-induced IL-12 was lower in the absence of MyD88, the cytokine was nonetheless required to induce type I immunity. Type 1 and type 3 innate lymphoid cells (ILC), CD4+ T cells, and CD8+ T cells each contributed to the IFN-γ pool. Furthermore, bacterial flagellin and Toxoplasma specific CD4+T cell populations in the lamina propria expanded to similar frequencies observed in the wildtype small intestine. ILC3 were expanded in both naïve and infected MyD88−/− mice relative to their MyD88+/+ counterparts, suggesting a compensatory response triggered by loss of MyD88. This study identifies MyD88-independent intestinal immune pathways induced by T. gondii including myeloid cell derived IL-12 production, downstream type I immunity, and IFN-γ production by ILC1, ILC3, and T lymphocytes. Collectively, these data reveal an underlying network of immune responses that do not involve MyD88 but that contribute to pathways associated with resistance to T. gondii.