T-bet-dependent ILC1-and NK cell-derived IFN-γ mediates cDC1-dependent host resistance against Toxoplasma gondii

Author summary Mounting 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 lymphoid 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 innate immune cells defends against T. gondii remains unknown. In this work, we identified that early T-bet-dependent production of IFN-gamma by ILC1 and NK cells is essential for maintaining dendritic cells (DCs) during infection. Mechanistically, we reveal that T-bet controlled innate 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. 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 and to a lesser degree NK, but not T(H)1 cells, were involved in the regulation of inflammatory DCs via IFN-gamma. Mechanistically, we established that T-bet dependent innate 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 T-bet dependent production of IFN-gamma by ILC1 and NK cells is indispensable for host resistance against intracellular infection via maintaining IRF8+ inflammatory DCs at the site of infection.

Automated summary

The study demonstrates that early T-bet-dependent production of IFN-gamma by ILC1 and NK cells is essential for maintaining inflammatory DCs during infection, ultimately contributing to host resistance against the parasite Toxoplasma gondii. T-bet-dependent IFN-gamma plays a critical role in inducing IRF8 and sustaining inflammatory DCs at the infection site, protecting against acute susceptibility to T. gondii infection.