Abstract
The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for TH2 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 TH1 cells. After transfer into infected mice, IRF4−/− CD4+ T cells failed to differentiate into TH1 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 TH1 differentiation of IRF4−/− CD4+ T cells. Our study identifies IRF4 as central regulator of TH1 responses and cellular metabolism. We propose that this function of IRF4 is fundamental for the initiation and maintenance of all TH cell responses.
Highlights
Factors involved in effector cell differentiation including Tbx[21], Prdm[1], Runx[3] and Tcf[7], as well as effector proteins such as cytokines and cytolytic proteins[11,25,26]
Interferon Regulatory Factor 4 (IRF4)−/− mice were infected with LmOVA, a L. monocytogenes strain recombinant for ovalbumin[37], and after 8 days the CD4+ TH1 response was analyzed
Following LLO189-201 stimulation, approx. 2% of CD4+ T cells from infected Wild type (WT) mice responded with up-regulation of CD40L and more than half of these cells co-expressed high levels of IFN-γand TNF-α, a hallmark of TH1 cells
Summary
Factors involved in effector cell differentiation including Tbx[21] (encoding T-bet), Prdm[1] (encoding BLIMP1), Runx[3] and Tcf[7] (encoding TCF-1), as well as effector proteins such as cytokines and cytolytic proteins[11,25,26]. IRF4 is involved in the metabolic changes of CD8+ T cells following activation. T cell activation causes enhanced nutrient uptake as well as increased aerobic glycolysis and glutaminolysis. These changes in the metabolic profile are necessary to provide energy and substrates for de novo synthesis of proteins, nucleic acids and lipids required for proliferation and effector protein production[33,34,35,36]. We use the Listeria monocytogenes infection model to analyze the role of IRF4 in TH1 cell differentiation and function. Compared to control cells, activated IRF4−/− CD4+ T cells exhibited impaired aerobic glycolysis and oxidative phosphorylation and this restricted metabolism could be responsible for the poor response of these cells
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