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The IL-27 p28 Subunit Binds Cytokine-Like Factor 1 to Form a Cytokine Regulating NK and T Cell Activities Requiring IL-6R for Signaling

2009; American Association of Immunologists; Volume: 183; Issue: 12 Linguagem: Inglês

10.4049/jimmunol.0901464

1550-6606

Sandrine Crabé, Angélique Guay-Giroux, Aurélie Tormo, Dorothée Duluc, Rami Lissilaa, François Guilhot, Ulrick Mavoungou-Bigouagou, Fouad Lefouili, Isabelle Cognet, Walter Ferlin, Greg Elson, Pascale Jeannin, Jean‐François Gauchat,

T-cell and B-cell Immunology

Abstract IL-27 is formed by the association of a cytokine subunit, p28, with the soluble cytokine receptor EBV-induced gene 3 (EBI3). The IL-27R comprises gp130 and WSX-1. The marked difference between EBI3−/− and WSX-1−/− mice suggests that p28 has functions independent of EBI3. We have identified an alternative secreted complex formed by p28 and the soluble cytokine receptor cytokine-like factor 1 (CLF). Like IL-27, p28/CLF is produced by dendritic cells and is biologically active on human NK cells, increasing IL-12- and IL-2-induced IFN-γ production and activation marker expression. Experiments with Ba/F3 transfectants indicate that p28/CLF activates cells expressing IL-6Rα in addition to the IL-27R subunits. When tested on CD4 and CD8 T cells, p28/CLF induces IL-6Rα-dependent STAT1 and STAT3 phosphorylation. Furthermore, p28/CLF inhibits CD4 T cell proliferation and induces IL-17 and IL-10 secretion. These results indicate that p28/CLF may participate in the regulation of NK and T cell functions by dendritic cells. The p28/CLF complex engages IL-6R and may therefore be useful for therapeutic applications targeting cells expressing this receptor. Blocking IL-6R using humanized mAbs such as tocilizumab has been shown to be beneficial in pathologies like rheumatoid arthritis and juvenile idiopathic arthritis. The identification of a new IL-6R ligand is therefore important for a complete understanding of the mechanism of action of this emerging class of immunosuppressors.