Interleukin-21 stimulates antigen uptake, protease activity, survival and induction of CD4+ T cell proliferation by murine macrophages

Interleukin (IL)-21 is a T cell-derived cytokine which uses a heterodimeric receptor, composed of the common γ-chain (CD132) and an IL-21Rα-chain. IL-21 activates lymphoid T and B cells, modulates antibody production but also suppresses maturation of myeloid dendritic cells; however, its role in the differentiation and function of other myeloid cells remains less clear. In this study we analysed IL-21/IL-21Rα effects on macrophage (MΦ) differentiation and function. MΦ could be generated readily from bone marrow with MΦ-colony-stimulating factor in the presence of IL-21 (designated IL-21MΦ) or from IL-21Rα-/- mice. IL-21Rα-/- mice had normal MΦ numbers, suggesting a non-essential role of both IL-21 and the IL-21Rα for MΦ generation. We could demonstrate that mature MΦ express the IL-21Rα and the common γ-chain. However, short-term IL-21 stimulation did not enhance MΦ proliferation but induced anti-apoptotic cell-cycle regulators p21 waf1/p27Kip1 and expression of suppressors of cytokine signalling (SOCS)2/SOCS3. Moreover, IL-21 enhanced phagocytosis by MΦ via IL-21Rα signalling and supports protease activity and matrix metalloproteinase 12 expression. Stimulating MΦ with IL-21 enhanced their capacity to induce antigen-specific CD4+ T cell proliferation in dependence from the IL-21Rα, which was not the case for CD8+ T cells. Taken together, IL-21 plays a previously unrecognized role in modulating innate and acquired effector mechanisms of murine MΦ by linking these different functions to support CD4+ T cell-mediated immune responses. © 2008 The Author(s).