title: Innate pro-B-cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells.
abstract: Diverse hematopoietic progenitors, including myeloid populations arising in inflammatory and tumoral conditions and multipotent cells, mobilized by hematopoietic growth factors or emerging during parasitic infections, display tolerogenic properties. Innate immune stimuli confer regulatory functions to various mature B-cell subsets but immature B-cell progenitors endowed with suppressive properties per se or after differentiating into more mature regulatory B cells remain to be characterized. Herein we provide evidence for innate pro-B cells (CpG-proBs) that emerged within the bone marrow both in vitro and in vivo upon Toll-like receptor-9 activation and whose adoptive transfer protected nonobese diabetic mice against type 1 diabetes (T1D). These cells responded to IFN-γ released by activated effector T cells (Teffs), by up-regulating their Fas ligand (FasL) expression, which enabled them to kill Teffs through apoptosis. In turn, IFN-γ derived from CpG-proBs enhanced IFN-γ while dramatically reducing IL-21 production by Teffs. In keeping with the crucial pathogenic role played by IL-21 in T1D, adoptively transferred IFN-γ-deficient CpG-proBs did not prevent T1D development. Additionally, CpG-proBs matured in vivo into diverse pancreatic and splenic suppressive FasL(high) B-cell subsets. CpG-proBs may become instrumental in cell therapy of autoimmune diseases either on their own or as graft complement in autologous stem cell transplantation.
authors.affiliation: Faculté de Médecine Site Necker, Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, 75015 Paris, France.
authors.forename: Ruddy
authors.initials: R
authors.lastname: Montandon
authors.forename: Sarantis
authors.initials: S
authors.lastname: Korniotis
authors.forename: Esther
authors.initials: E
authors.lastname: Layseca-Espinosa
authors.forename: Christophe
authors.initials: C
authors.lastname: Gras
authors.forename: Jérôme
authors.initials: J
authors.lastname: Mégret
authors.forename: Sophie
authors.initials: S
authors.lastname: Ezine
authors.forename: Michel
authors.initials: M
authors.lastname: Dy
authors.forename: Flora
authors.initials: F
authors.lastname: Zavala
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D020297:Mice, Congenic; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: C526902:CpG ODN 2216; D053222:Fas Ligand Protein; D007378:Interleukins; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma; D000098546:Interleukin-21
keywords: B lymphocytes; MyD88 signaling; T lymphocytes; immune therapy; peripheral tolerance