IL-33 promotes innate lymphoid cell-dependent IFN-γ production required for innate immunity to <i>Toxoplasma gondii</i>.

Abstract

IL-33 is an alarmin required for resistance to the parasite <i>Toxoplasma gondii</i>, but its role in innate resistance to this organism is unclear. Infection with <i>T. gondii</i> promotes increased stromal cell expression of IL-33, and levels of parasite replication correlate with release of IL-33 in affected tissues. In response to infection, a subset of innate lymphoid cells (ILC) emerges composed of IL-33R⁺ NK cells and ILC1s. In <i>Rag1^-/-</i>mice, where NK cells and ILC1 production of IFN-γ mediate innate resistance to <i>T. gondii</i>, the loss of the IL-33R resulted in reduced ILC responses and increased parasite replication. Furthermore, administration of IL-33 to <i>Rag1^-/-</i> mice resulted in a marked decrease in parasite burden, increased production of IFN-γ, and the recruitment and expansion of inflammatory monocytes associated with parasite control. These protective effects of exogenous IL-33 were dependent on endogenous IL-12p40 and the ability of IL-33 to enhance ILC production of IFN-γ. These results highlight that IL-33 synergizes with IL-12 to promote ILC-mediated resistance to <i>T. gondii</i>.