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Role of IL-21 in regulation of leukocyte functions

Immune system protects body from invading pathogens and other microbes. The immune system consists of white blood cells, leukocytes, which form a complex network along with soluble mediators, cytokines, by which the cells communicate with each other. In addition to secreted soluble mediators, the cells have also direct interactions with each other via their cell surface receptors. The immune system can be divided into two parts, innate and adaptive immunity. Innate immunity, which consists of complement system, phagocytic cells, e.g. granulocytes and macrophages, and natural killer cells, are activated within the first hours after infection. The activation of innate immunity does not require specific antigen recognition but the recognition of conserved microbial structures or molecules (e.g. dsRNA) that are abundant in microbes but missing in the host. These structures are recognized by for example Toll-like receptors (TLR). On the contrary, adaptive immunity includes the specific antigen recognition by B and T cells. B cells can bind antigens directly but T cell activation requires presentation of the antigen by macrophages or dendritic cells in association with MHC molecules. After antigen recognition T (and B) cells get activated, proliferate and start to destroy infected cells. Effective communication between the cells of the immune system is essential for the proper function of the whole complex network. Cells secrete cytokines that mediate signals between the cells. These signals lead to alterations in the gene expression of the target cell. Tens of different cytokines can be divided into several groups based on their structure, function, or the structure of the receptors they are binding. Common gamma-chain receptor family contains the cytokines IL-2, IL-4, IL-7, IL9, IL-15, and IL-21. IL-21 is the newest member of this family. It is produced by activated T cells and it affects the function of T cells in many ways. IL-21 also enhances the cytotoxic activity of NK cells towards e.g. virus-infected cells. In this study the regulatory role of IL-21 on human primary T and NK cells was studied. The effect of IL-21 on the regulation of certain Th1 and innate immunity genes was analyzed. We found out that IL-21 upregulated the expression of IL-2R, IL-12R, and IL-18R in NK and T cells, which enhaces the responsiveness of these cells to Th1 cytokines. Further IL-21 enhanced the gene expression as well as protein production of IFN-γ. IFN-γ production was synergistically enhanced by IL-21 and IL-15 costimulation. Also IL-21 and IL-18 synergistically enhanced NK and T cell IFN-γ production. Activation of gene expression requires the activation and binding of transcription factors to the promoter of the target gene. Janus kinases (Jak) and Signal transducer and activator of transcription (STAT) form an important signaling pathway, which is activated by cytokine stimulus. IL-21 stimulation of NK and T cells preferentially activated STAT3. Also STAT3-associated Jak1 and Jak3 kinases were activated. IL21 induced STAT1 and STAT4 activation and DNA binding too. This could be verified both by detecting the induced tyrosine phosphorylation of Jak and STAT proteins and analyzing the binding of STATs to the promoter of several target genes e.g. IL-2Rα. IFN-α/β is produced during virus infection by macrophages and dendritic cells. IFNα/β has direct anti-viral effects but it also enhances NK cell cytotoxic activity and T cell activation thus promoting both innate and adaptive immune responses. The regulatory role of IFN-α/β on IL-21 production from T cells was analyzed. IFN-α/β enhanced the expression of IL-21 in T cells. A sequence analysis of IL-21 promoter revealed a putative STAT binding element, which indeed bound STAT proteins after IFN-α stimulation. IFN-α/β also negatively regulates IL-21 functions by downregulating IL-21R expression in NK and T cells. This reduced responsiveness to IL21 leads to inhibited STAT3 activation by IL-21. Dendritic cells present antigens to T cells and are thus an important part of adaptive immunity. Dendritic cells can be obtained in vitro from primary monocytes by stimulating cells with GM-CSF and IL-4. In differentiating DCs the expression of IL-21R was induced but it remained at very low level in differentiating macrophages. Differentiated DCs are immature until they meet microbe or their component, such as LPS. Mature DCs up-regulate the expression of HLA and CD86 surface molecules and secrete cytokines and chemokines. Pretreatment of DCs with IL-21 inhibited LPS-induced DC maturation and cytokine production. LPS is recognized by TLR4 but we could not observe any reduction in the expression of TLR4 or its signaling components after IL-21 stimulation. However, IL-21 induced the expression of SOCS1 and SOCS3 genes. SOCS1 has previously been reported to inhibit LPS-induced TLR4 signaling and DC maturation. The results obtained in this study demonstrate that IL-21 has and important regulatory functions in human NK and T cells and DCs.