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

Abstract

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 B(reg) cells). Arising from CD19+ B cells, GIFT15 B(reg) 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 B(reg) 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 B(reg) cells paralleled by suppressed neuroinflammation. The clinical effect was abolished when GIFT15 B(reg) cells were derived from mmicroMT (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 B(reg) cells may serve as a new treatment for autoimmune ailments.

Regulatory B Cells - Implications in Autoimmune and Allergic Disorders

“…Furthermore, adoptive transfer experiments revealed a possible therapeutic potential of isolated regulatory B cells in EAE (Mann, Maresz et al 2007;Matsushita, Yanaba et al 2008;Rafei, Hsieh et al 2009;Kala, Rhodes et al 2010). Considering the extensive use of MS treatments that are dependent on B cell depletion, it seems crucial to define this dual role of B cells in the progression of disease.…”

GM-CSF–Based Fusion Cytokines as Ligands for Immune Modulation

“…Astonishingly, naive B cells responsive to GIFT-15 adopted an IL-10 + , B regulatory phenotype and are key mediators of GIFT-15's immune-suppressive capabilities. Indeed, GIFT-15-treated autologous B cells were used therapeutically to cure mice afflicted with EAE (45). GIFT-21: a hyperagonist for IL-21R-expressing APCs.…”

Une cytokine chimérique au secours des maladies auto-immunes

“…Nous avons observé que la fusokine chimère GIFT15 transforme les lympho cytes B naïfs en cellules suppressives B reg (Figure 1). Les cellules B reg exercent, comme les cellules T reg mieux connues, un rôle immunosuppresseur, mais elles s'en distinguent par leur abondante production d'IL-10 [9]. L'idée d'utiliser GIFT15 pour amplifier une population de B reg qui pourrait être ensuite être administrée comme une thérapie cellulaire autologue nous paraissait séduisante, et nous avons testé cette stratégie et l'effet pharmaceutique des B reg ainsi obtenus dans un modèle murin de sclérose en plaques [9].…”