Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naïve vs. effector/memory CD4⁺ T cells

Interferon regulatory factor (IRF) 4 is a member of the IRF family of transcription factors and plays critical roles in the development of CD4⁺ T cells into Th2 and Th17 cells. Using the infection model of Nippostrongyrus brasiliensis, we have confirmed the critical roles of IRF-4 in Th2 development in vivo by using IRF-4⁻/⁻ BALB/c mice. However, naïve IRF-4⁻/⁻CD4⁺ T cells produced Th2 cytokines, including IL-4, IL-5, and IL-10, but not IL-2 or IFN-γ, at levels higher than wild-type BALB/c CD4⁺ T cells in response to T cell receptor stimulation. In contrast, effector/memory IRF-4⁻/⁻CD4⁺ T cells did not exhibit increased production of Th2 cytokines. Knockdown of IRF-4 expression by using small interfering RNA promoted IL-4 production in naïve CD4⁺ T cells but inhibited it in effector/memory CD4⁺ T cells. These results indicate that IRF-4 plays differential roles in the regulation of Th2 cytokine production in naïve CD4⁺ T cells and effector/memory CD4⁺ T cells. IRF-4 inhibits Th2 cytokine production in naïve CD4⁺ T cells, whereas it promotes Th2 cytokine production in effector/memory CD4⁺ T cells.