Mature IgD^low/- B cells maintain tolerance by promoting regulatory T cell homeostasis

A number of different B cell subsets have been shown to exhibit regulatory activity using a variety of mechanisms to attenuate inflammatory diseases. Here we show, using anti-CD20-mediated partial B cell depletion in mice, that a population of mature B cells distinguishable by IgD^low/- expression maintains tolerance by, at least in part, promoting CD4⁺Foxp3⁺ regulatory T cell homeostatic expansion via glucocorticoid-induced tumor necrosis factor receptor ligand, or GITRL. Cell surface phenotyping, transcriptome analysis and developmental study data show that B cells expressing IgD at a low level (BD_L) are a novel population of mature B cells that emerge in the spleen from the transitional-2 stage paralleling the differentiation of follicular B cells. The cell surface phenotype and regulatory function of BD_L are highly suggestive that they are a new B cell subset. Human splenic and peripheral blood IgD^low/- B cells also exhibit BD_L regulatory activity, rendering them of therapeutic interest.