Interferon Regulatory Factor 4 controls T(H1) cell effector function and metabolism

The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for T(H2) and T(H17) cell formation and controls peripheral CD8(+) T cell differentiation. We used Listeria monocytogenes infection to characterize the function of IRF4 in T(H1) 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-γ 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 T(H) cell responses.