IL-10+ plasma cell mediated control of innate immunity

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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.