Faculté de Médecine Site Necker, Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, 75015 Paris, France.
Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):E2199-208. doi: 10.1073/pnas.1222446110. Epub 2013 May 28.
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.
多种造血祖细胞，包括在炎症和肿瘤条件下产生的髓系细胞以及造血生长因子动员或寄生虫感染过程中出现的多能细胞，显示出耐受性。先天免疫刺激赋予各种成熟 B 细胞亚群调节功能，但本身具有抑制特性的未成熟 B 细胞祖细胞或分化为更成熟的调节性 B 细胞后仍有待表征。在此，我们提供了证据表明，在体外和体内，Toll 样受体-9 激活后，骨髓中出现了先天前 B 细胞（CpG-proBs），其过继转移可保护非肥胖型糖尿病（NOD）小鼠免受 1 型糖尿病（T1D）的侵害。这些细胞对激活的效应 T 细胞（Teffs）释放的 IFN-γ做出反应，通过上调其 Fas 配体（FasL）的表达，使它们能够通过细胞凋亡杀死 Teffs。反过来，CpG-proBs 产生的 IFN-γ增强了 IFN-γ，同时显著降低了 Teffs 产生的 IL-21。与 IL-21 在 T1D 中发挥的关键致病作用一致，过继转移的 IFN-γ 缺陷型 CpG-proBs 不能预防 T1D 的发展。此外，CpG-proBs 在体内成熟为各种胰腺和脾脏抑制性 FasL（高）B 细胞亚群。CpG-proBs 可能成为自身免疫性疾病细胞治疗的工具，无论是单独使用还是作为自体干细胞移植的移植物补充。
