Type I and type II interferons (IFN) have critical roles in host defense and immunoregulation, with some aspects of their actions overlapping and others being quite distinct. In this study, we compared the actions of type I (IFN-beta) and type II (IFN-gamma) IFN on CD4 T cells, and found that T-bet has a profound impact on the distinct transcriptomes and metabolic profiles triggered by these cytokines. T-bet has been well described as a lineage defining transcription factor (LDTF) for T helper 1 (Th1) cells that regulates IFN-gamma production. However, little is known about its role beyond determining lineage. Here, we found that in the absence of T-bet, IFN-gamma aberrantly enhanced STAT2 activity and a type I IFN transcriptomic program, while reducing glycolysis. Moreover, during the Th1 response induced in vivo by Toxoplasma infection, type I IFN signature genes were enhanced in T-bet deficient CD4 T cells compared with wild type cells. We found that T-bet restrained the type I IFN signature otherwise triggered by IFN-gamma by inhibiting autocrine production of type I IFNs as well as constraining STAT1, STAT2 and IRF7 expression. Accordingly, blocking the type I IFN receptor (IFNAR) during IFN-gamma treatment inhibited the type I IFN signature and restored glycolytic capacity in T-bet deficient cells. This inhibitory activity of T-bet on multiple components of the type I IFN circuitry ensures the development of a polarized type II IFN response and appropriate effector cell expansion in Th1-dominated infections.
This work was supported by the intramural research programs of NIAMS and the NIAID.