IL-10+ plasma cell mediated control of innate immunity

最近的研究表明，通过IL-10的产生，以生发中心非依赖性方式形成的分泌抗体的B谱系细胞可以有效地控制T细胞介导的自身免疫和炎症，并表现出浆母细胞的CD 138+表型。有人认为，这些“调节性”浆母细胞类似于未成熟/调节性B细胞的直接后代，尽管这个问题迄今尚未澄清。相比之下，我们小组目前的工作表明，免疫调节性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，并且也在鼠和人骨髓瘤细胞中观察到。因此，表明IL-10的产生和调节特性不限于浆母细胞的某个子集，而是在各种条件下产生的浆母细胞/浆细胞的更一般的特征。此外，我们发现浆细胞来源的IL-10不仅可以调节炎性T细胞应答，而且还直接下调中性粒细胞功能，并且这种机制对于在浆细胞增多症相关疾病中观察到的临床相关免疫缺陷和感染易感性增加的发展是重要的。我们的初步数据表明，浆细胞IL-10也有相当大的影响单核细胞巨噬细胞的分化和他们的炎症/抗炎功能，这是已经观察到在生理条件下。在这个建议中，我们的目的是测试我们的假设，即IL-10+“调节性浆细胞”是来自未成熟/调节性B细胞或其他B细胞类型，这取决于各自免疫反应的背景;并且这些细胞直接对先天效应细胞具有深远的影响。将研究IL-10+浆细胞与IL-10-浆细胞和其他B细胞亚型的表型、归巢能力、寿命/成熟阶段和克隆关系。浆细胞衍生的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后果将在生理条件下、在无菌浆细胞增多症的背景下和在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.