Cutting edge:: T-bet and IL-27R are critical for in vivo IFN-γ production by CD8 T cells during infection

CD8(+) T cells are a major source of IFN-gamma, a key effector cytokine in immune responses against many viruses and protozoa. Although the transcription factor T-bet is required for IFN-gamma expression in CD4(+) T cells, it is reportedly dispensable in CD8(+) T cells, where the transcription factor Eomesodermin is thought to be sufficient. The diverse functions of IFN-gamma are mediated through the IFN-gamma R and STAT1. In CD4(+) T cells, STAT1 appears to be critical for the activation of T-bet and IFN-gamma, suggesting an IFN-gamma-dependent positive feedback loop. However, STAT1 can also be activated by other cytokines, including IL-27. In the present study we show that, in contrast to in vitro conditions and the prevailing paradigm, T-bet is critical for the in vivo IFN-gamma production by CD8(+) T cells upon infection of mice with diverse pathogens. Whereas IFN-gamma R signals are dispensable for the T-bet-dependent IFN-gamma production, direct IL-21R alpha signals are critical.