IRF4 Couples Anabolic Metabolism to Th1 Cell Fate Determination

Anabolic metabolism in lymphocytes promotes plasmablast and cytotoxic T cell differentiation at the expense of self-renewal. Heightened expression and function of the transcription factor IFN regulatory factor 4 (IRF4) accompany enhanced anabolic induction and full commitment to functional differentiation in B cells and CD8⁺ T cells. In this study, we used a genetic approach to determine whether IRF4 plays an analogous role in Th1 cell induction. Our findings indicate that IRF4 promotes determined Th1 cell differentiation in tandem with anabolic metabolism of CD4⁺ T cells. IRF4-deficient CD4⁺ T cells stimulated in vitro exhibit impaired induction of Th1 gene expression and defective silencing of T cell factor 1 expression. IRF4-deficient CD4⁺ T cells also undergo a shift toward catabolic metabolism, with reduced mammalian target of rapamycin activation, cell size, and nutrient uptake, as well as increased mitochondrial clearance. These findings suggest that the ability to remodel metabolic states can be an essential gateway for altering cell fate.