A granulocyte-macrophage colony–stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties

Rafei et al. Nature Medicine. 15, 1038-1045

Speaker: 李建勳                                                  Time:14:00-15:00 02/24 2010

Commentator: 黎煥耀 老師                              Place: Room 601

Abstract:

Granulocyte-macrophage colony–stimulating factor (GM-CSF) enhances antigen presentation and costimulation, and interleukin (IL)-15 regulates activation and proliferation of T cells and natural killer cells. The authors previously fused these two cytokines to generate a "fusokine" GIFT15, but unexpectedly, GIFT15 exerted suppressive rather than stimulatory effects on immune response both in vitro and in vivo. This study was to further explore the mechanism of GIFT15-mediated immunosuppression and to evaluate its therapeutic impact. Treatment of mouse splenocytes with GIFT15 induced a unique cell population expressing MHC class I, MHC class II, B220, and an immunosuppressive cytokine IL-10. This cell popultaion arose from CD19 B cells and was phenotypically similar to B10 or T2-MZP regulatory B (Breg) cells. The GIFT15-induced, IL-10-producing Breg cells expressed lower amount of interferon (IFN)-g, IL-2 and IL-12 upon activation, and functionally suppressed IFN-g�nproduction from T cells in both mixed lymphocyte reaction and antigen-specific stimulation. In a mouse model of experimental autoimmune encephalomyelitis (EAE), ex vivo injection of GIFT15-induced Breg cells completely reversed the disease score, reduced infiltration of myeloid and CD4 T cells in central nerve system, and suppressed T cell reactivation stimulated by pathogenic peptides. Using MHC-mismatched or gene-knockout mice, the authors revealed that the immunosuppressive functions of GIFT15-induced Breg cells required IL-10, STAT6, and the syngeneic properties of the cells. Therefore, autologous GIFT15-induced Breg may serve as a novel therapeutic approach for autoimmune diseases.

References:

1. Rafei et al. A GMCSF and IL-15 fusokine leads to paradoxical immunosuppression in vivo via asymmetrical JAK/STAT signaling through the IL-15 receptor complex. Blood. 109, 2234–2242 (2007).