IL‐27 induction of IL‐21 from human CD8 + T cells induces granzyme B in an autocrine manner

Interleukin (IL)‐27 exerts an anti‐inflammatory effect on human and mice CD4 + T cells by inducing IL‐10‐producing T regulatory 1 cells through induction of IL‐21. However, the role of IL‐27 and how it regulates IL‐21 from human CD8 + T cells is unclear. Here, we show that the IL‐27 receptor is expressed on human CD8 + T cells and stimulation of human naïve CD8 + T cells in the presence of IL‐27 leads to an increase in IL‐21 and interferon (IFN)‐γ production. IL‐21 induction in IL‐27‐stimulated human CD8 + T cells correlates specifically with expression of the transcription factor T‐bet. IL‐27 stimulation of naïve CD8 + T cells induces a double‐positive T‐bet + IL‐21 + expressing CD8 + T‐cell population. Furthermore, IL‐27 stimulation of human naïve CD8 + T cells greatly increases expression of granzyme B. Antibody‐mediated neutralization of IL‐21 abrogates IL‐27‐induced granzyme B expression. Moreover, direct addition of IL‐21 greatly amplifies granzyme B expression in human naïve CD8 + T cells. Our findings identify IL‐27‐induced IL‐21 as a key autocrine regulator of granzyme B expression in human CD8 + T cells.