MDSCs诱导高分泌IL-10调节性B细胞的产生及其机制

Myeloid derived suppressor cells (MDSCs) are one of the main cell populations responsible for regulating immune responses. MDSCs accumulate during tumor progression, chronic infection and other pathological conditions and can potently suppress T-cell and NK-cell functions. More recently, we observed that MDSCs induced the differentiation of LPS-activated B cells into IL-10-producing B cells, suggesting that MDSCs may exert its negative regulatory function by inducing regulatory B cell generation. In this study, we will further determine whether MDSCs can induce regulatory B cell generation in vitro and in vivo and what are the underlying mechanisms. Furthermore, we will investigate the origins, phenotypes and functional characteristics of these IL-10-secreting B cells after being cocultured with MDSCs. Moreover, we will explore the roles of MDSCs and regulatory B cells induced by MDSCs during sepsis. Our study may provide a new manner of MDSCs for negative control of T-cell immune response and maintenance of immune homeostasis by, at least partially, inducing differentiation of B cells into regulatory B cells. In addition, this study could be useful to better understand the origin and developmental pathways of regulatory B cells and may be helpful for predicting the disease prognosis and targeting treatment strategies in patients with sepsis.

髓系抑制性细胞（MDSC）是一群具有很强免疫抑制功能的细胞，在肿瘤和炎症等疾病的进展和转归过程中起着重要调节作用。但以往的研究主要集中于它们对T细胞和NK等细胞免疫应答的调控作用。我们新近观察到MDSC能够诱导LPS活化的B细胞高分泌IL-10，提示MDSC很可能还具有调控B细胞亚群分化的新功能。本课题拟通过体内和体外实验进一步明确MDSC是否可诱导高分泌IL-10调节性B细胞亚群的产生以及这些B细胞的来源、表型和功能特征；鉴定出诱导调节性B细胞亚群产生的MDSC亚群并阐明其潜在分子机制；同时，结合LPS休克模型和脓毒症患者外周血标本检测，探讨MDSC及其诱导产生的调节性B细胞在脓毒症进展和转归过程中的作用。所得的结果不仅可揭示MDSC负向调控免疫应答多细胞网络的新机制，有助于我们更好地理解调节性B细胞亚群的来源与分化机制，还可为脓毒症的预后评估和新型治疗手段的研制提供新的理论基础。

髓系抑制性细胞（MDSC）是一群具有很强免疫抑制功能的细胞，在肿瘤和炎症等疾病的进展和转归过程中起着重要调节作用。但以往的研究主要集中于它们对T 细胞和NK 等细胞免疫应答的调控作用。本项目的研究发现，粒系和单核细胞系MDSC均可以诱导LPS 活化的B 细胞高分泌IL-10，该B细胞的表型为CD19hiFcγRIIbhi，可通过分泌IL-10抑制活化T细胞的增殖，但不能诱导调节性T细胞的分化。脾脏T1、T2、T3和MZ B细胞均可被诱导为CD19hiFcγRIIbhi的调节性B细胞，其中MZ B细胞分化后的调节性B细胞分泌IL-10的水平最高。过继回输CD19hiFcγRIIbhi B细胞可以明显促进荷瘤小鼠肿瘤的生长。MDSC分泌的PGE2参与诱导B细胞高分泌IL-10这一过程，但PGE2并不能直接诱导B细胞高分泌IL-10，进一步研究发现MDSC诱导B细胞高分泌IL-10需要膜接触。本研究所得的结果不仅揭示了MDSC负向调控免疫应答多细胞网络的新机制，也有助于我们更好地理解调节B 细胞亚群的来源与分化机制。