IFN- 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-2R and IL-15R . These receptors also share a common cytokine receptor -chain with IL-4, IL-7, and IL-9. Macrophageor dendritic cell-derived interferon (IFN)/ is a key cytokine in regulation of NK and T cell functions. We demonstrate here that in addition to activating IFNgene expression, IFN/ and IL-12 enhance the mRNA expression of IL-21 in activated human T cells. In addition, IFN/ enhanced T cell receptor stimulation-induced IL-21 and IFNgene expression in resting T cells. The promoter analysis of IL-21 gene revealed a putative IFNactivation site element, which was found to bind signal transducer and activator of transcription 1 (STAT1), STAT2, STAT3, and STAT4 proteins in IFN/ -stimulated NK or T cell extracts. In contrast to IL-21 expression, IFN/ down-regulated IL-21R mRNA expression in NK and T cells. IFN/ -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/ in the regulation of IL-21 response. J. Leukoc. Biol. 76: 416–422; 2004.