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


We have previously shown that a granulocyte-macrophage colony–stimulating factor (GM-CSF) and interleukin-15 (IL-15) 'fusokine' (GIFT15) exerts immune suppression via aberrant signaling through the IL-15 receptor on lymphomyeloid cells. We show here that ex vivo GIFT15 treatment of mouse splenocytes generates suppressive regulatory cells of B cell ontogeny (hereafter called GIFT15 Breg cells). Arising from CD19+ B cells, GIFT15 Breg cells express major histocompatibility complex class I (MHCI) and MHCII, surface IgM and IgD, and secrete IL-10, akin to previously described B10 and T2-MZP Breg cells, but lose expression of the transcription factor PAX5, coupled to upregulation of CD138 and reciprocal suppression of CD19. Mice with experimental autoimmune encephalomyelitis went into complete remission after intravenous infusion of GIFT15 Breg cells paralleled by suppressed neuroinflammation. The clinical effect was abolished when GIFT15 Breg cells were derived from mμMT (lacking B cells), MHCII-knockout, signal transducer and activator of transcription-6 (STAT-6)-knockout, IL-10–knockout or allogeneic splenocytes, consistent with a pivotal role for MHCII and IL-10 by sygeneic B cells for the observed therapeutic effect. We propose that autologous GIFT15 Breg cells may serve as a new treatment for autoimmune ailments.

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Figure 1: GIFT15 Breg cell phenotype.
Figure 2: GIFT15 leads to the development of Breg cells.
Figure 3: The biochemical responses of GIFT15 Breg cells.
Figure 4: Bystander inhibition by GIFT15 Breg cells.
Figure 5: Therapeutic effects of GIFT15 Breg cells.
Figure 6: Breg cells are highly efficient in reversing EAE.


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M.R. is a recipient of a Fonds de Recherches en Santé du Québec Scholarship, and J.G. is a Fonds de Recherches en Santé du Québec chercheur-boursier sénior. C.P. holds a Canada Research Chair in Immunobiology. This work was supported by the Canadian Institute of Health Research grant MOP-15017.

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M.R. designed the research plan, performed most experiments, analyzed results and wrote the manuscript. J.H. performed APC assays. S.Z. induced EAE. M.L. performed cell culture and ELISAs. K.F. and E.B. handled mice. M.-N.B. performed CFSE experiments. Y.K.Y. performed cell death and cell cycle experiments. C.P. analyzed results and provided guidance. J.G. designed the research plan, analyzed results and wrote the manuscript.

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Correspondence to Jacques Galipeau.

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Rafei, M., Hsieh, J., Zehntner, S. et al. A granulocyte-macrophage colony–stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties. Nat Med 15, 1038–1045 (2009). https://doi.org/10.1038/nm.2003

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