IFN‐α regulates IL‐21 and IL‐21R expression in human NK and T cells

Interleukin (IL)‐21 is a T cell‐derived cytokine that regulates innate and adaptive immune responses. IL‐21 receptor (IL‐21R), which is expressed in natural killer (NK) and T cells, is structurally homologous to IL‐2Rβ and IL‐15Rα. These receptors also share a common cytokine receptor γ‐chain with IL‐4, IL‐7, and IL‐9. Macrophage‐ or dendritic cell‐derived interferon (IFN)‐α/β is a key cytokine in regulation of NK and T cell functions. We demonstrate here that in addition to activating IFN‐γ gene expression, IFN‐α/β and IL‐12 enhance the mRNA expression of IL‐21 in activated human T cells. In addition, IFN‐α/β enhanced T cell receptor stimulation‐induced IL‐21 and IFN‐γ gene expression in resting T cells. The promoter analysis of IL‐21 gene revealed a putative IFN‐γ activation site element, which was found to bind signal transducer and activator of transcription 1 (STAT1), STAT2, STAT3, and STAT4 proteins in IFN‐α/β‐stimulated NK or T cell extracts. In contrast to IL‐21 expression, IFN‐α/β down‐regulated IL‐21R mRNA expression in NK and T cells. IFN‐α/β‐induced down‐regulation of IL‐21R expression resulted in reduced STAT3 phosphorylation and DNA binding after IL‐21 stimulation. In conclusion, our results suggest a novel role for IFN‐α/β in the regulation of IL‐21 response.