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-21Ralpha-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-21Ralpha effects on macrophage (MPhi) differentiation and function. MPhi could be generated readily from bone marrow with MPhi-colony-stimulating factor in the presence of IL-21 (designated IL-21MPhi) or from IL-21Ralpha-/- mice. IL-21Ralpha-/- mice had normal MPhi numbers, suggesting a non-essential role of both IL-21 and the IL-21Ralpha for MPhi generation. We could demonstrate that mature MPhi express the IL-21Ralpha and the common gamma-chain. However, short-term IL-21 stimulation did not enhance MPhi 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 MPhi via IL-21Ralpha signalling and supports protease activity and matrix metalloproteinase 12 expression. Stimulating MPhi with IL-21 enhanced their capacity to induce antigen-specific CD4+ T cell proliferation in dependence from the IL-21Ralpha, 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 MPhi by linking these different functions to support CD4+ T cell-mediated immune responses.
Rückert
R
R
Research Center Borstel, Department of Immunology and Cell Biology, Borstel, Germany. rene.rueckert@bayerhealthcare.com
Bulfone-Paus
S
S
Brandt
K
K
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000276:immunology; D053738:Interleukin-21 Receptor alpha Subunit / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010447:Peptide Hydrolases / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000098546:Interleukin-21
D018797:Cell Cycle Proteins; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D053762:Interleukin-12 Subunit p40; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D010447:Peptide Hydrolases; D000098546:Interleukin-21