IRF4 Modulates CD8⁺ T Cell Sensitivity to IL-2 Family Cytokines

IFN regulatory factor 4 (IRF4) is a key transcription factor that promotes effector CD8⁺ T cell differentiation and expansion. The roles of IRF4 in regulating the CD8⁺ T cell response to cytokines have not been explored. In this article, we show that IL-2 and IL-15 signaling and STAT5 activation regulate IRF4 expression in CD8⁺ T cells. Gene-expression profile analysis has also revealed that IRF4 is required for expression of the receptors of IL-2 family cytokines CD122 and CD127. We found that IRF4 binds directly to CD122 and CD127 gene loci, indicating that it may directly promote CD122 and CD127 gene transcription. As a consequence, IRF4-deficient CD8⁺ T cells show diminished sensitivity to IL-2, IL-15, and IL-7 treatment in vitro. Furthermore, we found that IRF4-deficient CD8⁺ T cells had lower expression of CD122 and CD127 in vivo during influenza virus infection. These data suggest that IRF4 regulates the sensitivity of CD8⁺ T cells to IL-2 family cytokines, which correlates with the diminished effector and memory CD8⁺ T cell responses in IRF4-deficient CD8⁺ T cells.