BACKGROUND. Interleukin (IL)-21 is the most recently described cytokine that signals via the common cytokine receptor (γc), is produced by activated CD4+ T-cells, and regulates expansion and effector function of CD8+ T-cells. MATERIALS. To explore the actions of IL-21 with other γc-dependent cytokines in alloreactivity, mRNA expression of IL-21, IL-21R α-chain, and IL-2 proliferation and cytotoxicity was measured after stimulation in mixed lymphocyte reactions. Additionally, IL-21 and IL-21R α-chain expression was studied in biopsies of heart transplant patients. RESULTS. Analysis of mRNA expression levels of allostimulated T-cells showed a 10-fold induction of IL-21 and IL-21R α-chain. Interestingly, induction of IL-21 was highly dependent on IL-2 (as in the presence of anti-IL-2, anti-IL-2R α-chain, and the immunosuppressive drugs cyclosporine A, tacrolimus, and rapamycin) the transcription of IL-21 was almost completely inhibited, whereas in the presence of exogenous IL-2 the mRNA expression of IL-21 was even more upregulated. IL-21 functioned as a costimulator for IL-2 to augment proliferation and cytotoxic responses, while blockade of the IL-2 route abrogated these functions of IL-21. Blockade of the IL-21 route by anti-IL-21R α-chain monoclonal antibodies inhibited the proliferation of alloactivated T-cells. Also, in vivo alloreactivity was associated with IL-21/IL-21R α-chain expression. After heart transplantation, the highest intragraft IL-21, IL-21R α-chain, and IL-2 mRNA expression levels were measured during acute rejection (P<0.001, P=0.01, P=0.03). CONCLUSION. IL-21 is a critical cytokine for IL-2 dependent immune processes. Blockade of the IL-21 pathway may provide a new perspective for the treatment of allogeneic responses in patients after transplantation.

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Keywords Allogeneic reactions, Heart transplantation, Immunosuppression, Interleukin-21
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Baan, C.C., Balk, A.H.M.M., Dijke, I.E., Korevaar, S.S., Peeters, A., de Kuiper, R., … Weimar, W.. (2007). Interleukin-21: An interleukin-2 dependent player in rejection processes. Transplantation, 83(11), 1485–1492. doi:10.1097/