Interferon Regulatory Factor 4 controls TH1 cell effector function and metabolism

The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for T-H2 and TH17 cell formation and controls peripheral CD8(+) T cell differentiation. We used Listeria monocytogenes infection to characterize the function of IRF4 in TH1 responses. IRF4(-/-) mice generated only marginal numbers of listeria-specific T-H1 cells. After transfer into infected mice, IRF4(-/-) CD4(+) T cells failed to differentiate into T-H1 cells as indicated by reduced T-bet and IFN-gamma expression, and showed limited proliferation. Activated IRF4(-/-) CD4(+) T cells exhibited diminished uptake of the glucose analog 2-NBDG, limited oxidative phosphorylation and strongly reduced aerobic glycolysis. Insufficient metabolic adaptation contributed to the limited proliferation and T-H1 differentiation of IRF4(-/-) CD4(+) T cells. Our study identifies IRF4 as central regulator of T-H1 responses and cellular metabolism. We propose that this function of IRF4 is fundamental for the initiation and maintenance of all TH cell responses.