Foxo1 shapes CD8+ T cells effector functions by modulating υc and IL4Rα expression in IL-4 signaling 4701

Description The common gamma chain (γc) is necessary to signal γc cytokines, including Interleukin (IL)-2, -4, -7, -9, -15, and -21. Although γc is crucial for the immune system, its expression mechanism remains unclear, as it was thought to be regulated by cytokine-specific receptor subunits. Here, we showed that only IL-4 of γc cytokines significantly upregulated the γc expression in lymph node (LN) T cells. First, to determine the pathway responsible for IL-4-induced γc upregulation, we evaluated IL-4-induced γc upregulation using mice deficient in key transcription factors, including STAT1, 3, 5, and 6 involved in IL-4 signaling, and inhibitors that specifically inhibit them. Surprisingly, IL-4-induced γc upregulation was comparable in STAT1, 3, 5, and 6-deficient and wild-type (WT) T cells. However, in Foxo1-deficient T cells, IL-4 upregulated γc and IL4Rα at the mRNA level but not at the protein level. Given the known importance of IL-4 and Foxo1 in CD8+ T cell-mediated anti-tumor effects, we evaluated the effects of IL-4-induced γc and IL4Rα upregulation on CD8+ T cells function. Using Foxo1KDOT-1 T cells, we found that this regulation influences their anti-tumor efficacy. In conclusion, we identified Foxo1 as a key regulator of IL-4-induced γc and IL4Rα translation and revealed its critical role in modulating CD8+ T cell effector functions. These findings highlight the pivotal role of γc and IL4Rα regulation in immune responses.