PI3K-Akt pathway enhances the differentiation of interleukin-27-induced type 1 regulatory T cells

Interleukin 27 (IL-27) has been identified as a potent cytokine in the differentiation of type 1 regulatory T (Tr1) cells through interactions with several key elements, including transcription factors such as aryl hydrocarbon receptor and IL-21. Autocrine production of IL-21 is known to be important for maintaining IL-10 expression by Tr1 cells. Although previous studies have shown that the phosphoinositide 3-kinase (PI3K) –Akt axis contributes to the differentiation of helper T-cell subsets, the role of the PI3K pathway on Tr1 cell differentiation remains to be elucidated. Here, we demonstrate that suppression of the PI3K-Akt pathway results in impairment of IL-27-induced Tr1 (IL-27–Tr1) cell differentiation in vitro and in vivo. Furthermore, this suppression down-regulates IL-21 receptor expression by Tr1 cells, followed by suppression of IL-10 expression by IL-27–Tr1 cells. These results suggest that the PI3K pathway enhances IL-10 expression by IL-27–Tr1 cells through up-regulation of IL-21 receptors.