Immuno-Regulation Laboratory, University General Hospital Gregorio Marañón, Health Research Institute Gregorio Marañón (IiSGM), Medicine and Experimental Surgery Building, Calle Máiquez, 9, 28009 Madrid, Spain.
Int J Mol Sci. 2018 Jun 12;19(6):1737. doi: 10.3390/ijms19061737.
Regulatory B cells (Bregs) participate in auto-tolerance maintenance and immune homeostasis. Despite their impact on many diseases and due to the difficulty to define them, knowledge about their origin and their physiological inducers is still unclear. The incomplete understanding about the generation of Bregs and their limited numbers in periphery make it difficult to develop Breg-based therapy. Therefore, identifying factors that promote their development would allow their ex-vivo production in order to create new immunotherapy. This project aims to test the capacity of several cytokines (Interleukin 1-beta (IL-1β), Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), and Cluster of differentiation 40 ligand (CD40L)) and bacteria-derived oligodeoxynucleotides (CpG-ODN), alone or in combination, to generate B cells with regulatory phenotype and function. We have demonstrated that the Breg-associated phenotypes were heterogeneous between one and other stimulation conditions. However, the expression of other markers related to Bregs such as IL-10, CD80, CD86, CD71, Programmed cell death-1 (PD-1), and Programmed death-ligand 1 (PD-L1) was increased when cells were stimulated with CpG alone or in combination. Moreover, stimulated B cells presented a suppressive function on autologous activated peripheral blood mononuclear cells (PBMC) proliferation. Therefore, this work is the first step to demonstrate the feasibility to induce functional Breg-like cells in vitro and will then facilitate the way to produce Breg-like cells as a potential future cellular therapy.
调节性 B 细胞（Bregs）参与自身耐受的维持和免疫稳态。尽管它们对许多疾病有影响，并且由于难以定义它们，关于它们的起源和生理诱导物的知识仍然不清楚。对 Bregs 的产生和其在外周的有限数量的不完全理解使得基于 Bregs 的治疗方法的发展变得困难。因此，确定促进其发展的因素将允许它们在体外产生，以创造新的免疫疗法。本项目旨在测试几种细胞因子（白细胞介素 1-β（IL-1β）、粒细胞巨噬细胞集落刺激因子（GM-CSF）和 CD40 配体（CD40L））和细菌衍生的寡脱氧核苷酸（CpG-ODN）单独或组合的能力，以产生具有调节表型和功能的 B 细胞。我们已经证明，在一种刺激条件和另一种刺激条件之间，Breg 相关表型是异质的。然而，当细胞仅用 CpG 或与其他物质组合刺激时，其他与 Bregs 相关的标记物（如白细胞介素 10（IL-10）、CD80、CD86、CD71、程序性细胞死亡-1（PD-1）和程序性死亡配体 1（PD-L1）的表达增加。此外，刺激后的 B 细胞对自身激活的外周血单个核细胞（PBMC）增殖具有抑制功能。因此，这项工作是首次证明在体外诱导功能性 Breg 样细胞的可行性，然后将为产生 Breg 样细胞作为一种潜在的未来细胞疗法铺平道路。
