IL-10+ plasma cell mediated control of innate immunity

最近的研究表明，通过产生IL-10，以不依赖生发中心的方式形成的具有CD138+表型的抗体分泌的B系细胞可以有效地控制T细胞介导的自身免疫和炎症。有人认为，这些“调节性”浆母细胞类似于未成熟/调节性B细胞的直系后代，尽管这个问题到目前为止还不清楚。相反，我们小组目前的工作表明，免疫调节IL-10的产生也在来自IGD+幼稚B细胞的浆母细胞和浆细胞中观察到，也在小鼠和人骨髓瘤细胞中观察到。因此，提示IL-10的产生和调节特性并不局限于浆母细胞的某个子集，而是在不同条件下产生的浆母细胞/浆细胞的更一般的特征。此外，我们发现血浆细胞来源的IL-10不仅可以调节炎性T细胞反应，还可以直接下调中性粒细胞的功能，这一机制对于临床相关免疫缺陷的发生和感染易感性的增加是重要的，在浆细胞增多症相关疾病中观察到。我们的初步数据表明，血浆细胞IL-10对单核巨噬细胞的分化及其炎症/抗炎功能也有相当大的影响，这是在生理条件下已经观察到的。在这项提议中，我们旨在检验我们的假设，即IL-10+“调节性浆细胞”来源于未成熟/调节性B细胞或来自其他类型的B细胞，取决于各自免疫反应的背景；这些细胞对先天效应细胞具有深刻的影响。将研究IL-10+浆细胞的表型、归巢能力、寿命/成熟阶段以及与IL-10-浆细胞和其他B细胞亚型的克隆关系。血浆细胞来源的IL-10对中性粒细胞和巨噬细胞功能的作用及其对免疫和炎症的影响将在生理条件下、无菌浆细胞增多症和感染期间进一步研究。

Recent studies showed that via IL-10 production, antibody-secreting B lineage cells formed in a germinal center independent manner and exhibiting a CD138+ phenotype of plasmablasts can efficiently control T cell mediated autoimmunity and inflammation. It was suggested that these "regulatory" plasmablasts resemble direct descendants of immature/regulatory B cells, though this issue could not be clarified so far. In contrast, current work from our group indicate that the production of immuno-regulatory IL-10 is also observed in plasmablasts and plasma cells derived from IgD+ naïve B cells, and also in murine and human myeloma cells. Hence, suggesting that IL-10 production and regulatory properties are not restricted to a certain subset of plasmablasts, but are more general features of plasmablasts/plasma cells generated under various conditions. Moreover, we showed that plasma cell derived IL-10 can not only regulate inflammatory T cell responses, but also directly down-modulates neutrophil functions, and that this mechanism is important for the development of clinically relevant immunodeficiency and increased susceptibility to infection, observed in plasmacytosis-associated diseases. Our preliminary data indicate that plasma cell IL-10 also has a considerable effect on monocyte macrophage differentiation and their inflammatory/anti-inflammatory functions, which is observed already under physiological conditions.In this proposal, we aim to test our hypothesis that IL-10+ "regulatory plasma cells" are derived either from immature/regulatory B cells or from other B cell types, depending on the context of the respective immune reaction; and that these cells have a profound effect directly on innate effector cells. Phenotype, homing capacities, lifetime/maturation stage and clonal relationship of IL-10+ plasma cells to IL-10- plasma cells and other B cell subtypes will be investigated. The role of plasma cell derived IL-10 on neutrophil and macrophage functions and its consequence for immunity and inflammation will be further studied under physiological conditions, in the context of sterile plasmacytosis and during infection.