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 gamma-chain (CD132) and an IL-21R alpha-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-21R alpha effects on macrophage (M Phi) differentiation and function. M Phi could be generated readily from bone marrow with M Phi-colony-stimulating factor in the presence of IL-21 (designated IL-21M Phi) or from IL-21R alpha(-/-) mice. IL-21R alpha(-/-) mice had normal M Phi numbers, suggesting a non-essential role of both IL-21 and the IL-21R alpha for M Phi generation. We could demonstrate that mature M Phi express the IL-21R alpha and the common gamma-chain. However, short-term IL-21 stimulation did not enhance M Phi proliferation but induced anti-apoptotic cell-cycle regulators p21(waf1)/p27(Kip1) and expression of suppressors of cytokine signalling (SOCS)2/SOCS3. Moreover, IL-21 enhanced phagocytosis by M Phi via IL-21R alpha signalling and supports protease activity and matrix metalloproteinase 12 expression. Stimulating M Phi with IL-21 enhanced their capacity to induce antigen-specific CD4(+) T cell proliferation in dependence from the IL-21R alpha, 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 M Phi by linking these different functions to support CD4(+) T cell-mediated immune responses.