ILC1-derived IFN-gamma mediates cDC1-dependent host resistance against Toxoplasma gondii

Abstract

Host resistance against intracellular pathogens requires a rapid IFN-{gamma} mediated immune response. We reveal that T-bet-dependent production of IFN-{gamma} is essential for the maintenance of inflammatory DCs at the site of infection with a common protozoan parasite, Toxoplasma gondii. A detailed analysis of the cellular sources for T-bet-dependent IFN-{gamma} identified that ILC1s, but not NK or TH1 cells, were involved in the regulation of inflammatory DCs via IFN-{gamma}. Mechanistically, we established that T-bet dependent ILC1-derived IFN-{gamma} is critical for the induction of IRF8, an essential transcription factor for cDC1s. Failure to upregulate IRF8 in DCs resulted in acute susceptibility to T. gondii infection. Our data identifies that ILC1-derived IFN-{gamma} is indispensable for host resistance against intracellular infection via maintaining IRF8+ inflammatory DCs at the site of infection. Author SummaryMounting a robust type I innate immune response is essential for resistance against numerous intracellular pathogens. The type I immune response is characterized by the production of IFN-{gamma}, a central cytokine required for multiple non-redundant effector functions against bacterial, viral, and parasitic pathogens. Previous work has shown that group 1 innate lymphocyte cells (ILC1s) together with NK and CD4+ T cells play an indispensable IFN-{gamma} mediated protective role against Toxoplasma gondii infection; yet, the pathway of how IFN-{gamma} produced by ILC1s defend against T. gondii remains unknown. In this work we identified that early production of IFN-{gamma} by ILC1 is essential for maintaining dendritic cells (DCs) during infection. Mechanistically, we reveal that ILC1-derived IFN-{gamma} is indispensable for inducing the transcription factor IRF8 that is critical for sustaining inflammatory DCs. Finally, we demonstrate that IRF8+ DCs are critical for parasite elimination.