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.