T-bet-expression in dendritic cells is essential for T. gondii clearance

Abstract

The host’s type I immune response is essential for resistance to diverse groups of intracellular pathogens, including Mycobacterium, Leishmania, Salmonella, and Toxoplasma gondii. Type I immunity is traditionally characterized by the transcription factor T-bet, encoded by Tbx21, which has been considered the master regulator of determining the lineage commitment of CD4+ T_H1 cells and their production of the effector molecule IFN-γ. However, recent studies by our and other groups have shown that T-bet expression in CD4+ T cells is dispensable for IFN-γ production, and that T-bet-independent T cell-derived IFN-γ is sufficient to cause immunopathology during infection. Despite comparable levels of IFN-γ generated by Tbx21^−/− mice, they remain highly susceptible to infection. Furthermore, Tbx21^−/− mice succumb significantly faster to T. gondii infection than animals lacking B and T cells, yet retain an intact myeloid innate compartment, suggesting that T-bet deficiency in innate immune cells results in loss of host resistance to intracellular parasite, and rapid host mortality during infection. Thus, we investigated T-bet expression levels in myeloid innate immune cells and observed that T-bet expression in monocyte-derived CD11c+ DCs occurs in an IFN-γ-dependent manner. We also established that T-bet expression in DCs, but not macrophages, is required for resistance to intracellular T. gondii infection. Overall, we revealed an essential role for T-bet expression in DCs for controlling host immunity to intracellular parasite infection.