Interferon Regulatory Factor 4 controls TH1 cell effector function and metabolism

Abstract

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.