IL‐4 induces a suppressive IL‐10‐producing CD8(+) T cell population via a Cdkn2a‐dependent mechanism

Zhao, Yapu; Zhao, Huiyuan; Sun, Yuehong; Hao, Jianlei; Qi, Xiaofei; Zhou, Xinglong; Wu, Zhenzhou; Wang, Puyue; Kaech, Susan M.; Weaver, Casey T.; Flavell, Richard A.; Zhao, Liqing; Yao, Zhi; Yin, Zhinan

CD8(+) T cells play an important role in immune regulation and effective immune responses against tumor cells, viral infection, and intracellular pathogens. In this report, using tiger or 10BiT mice, we defined a population of IL‐10‐producing CD8(+) T cells that were induced by IL‐4. These IL‐10(+)CD8(+) T cells possessed a strong inhibitory effect on the CD4(+) T cell proliferation in an IL‐10‐dependent and cell contact‐dependent fashion. In comparison with IL‐10(−)CD8(+) T cells, IL‐10(+)CD8(+) T cells expressed an array of Th2‐like cytokines (IL‐4, IL‐5), perforin, and granzymes, as well as the cell cycle regulatory protein Cdkn2a. Interestingly, knockdown of cdkn2a using siRNA reduced IL‐4‐induced IL‐10 production significantly. Furthermore, CD8(+) T cells from Cdkn2a(−/−) mice produced a significantly lower amount of IL‐10, and the effect was limited to CD8(+) T cells but not observed in CD4(+) T cells and APCs. Finally, IL‐10(+)CD8(+) T cells played a protective role in the TNBS‐induced murine colitis model, indicating a critical role of this population of CD8(+) T cells in regulatory immune responses. Taken together, we have defined a population of IL‐10‐producing CD8(+) Tregs induced by IL‐4 and mediated by Cdkn2a.