In humans, Bregs were first identified mainly as CD5+B1a cells, CD21+CD23–

marginal zone cells or CD1d+CD21+CD23+ T2-marginal zone precursor B cells [33]. Mauri and colleagues AZD1152-HQPA nmr narrowed down the core phenotype of at least one Breg population to CD19+CD24+/intermediateCD38+/intermediate which produces IL-10 [23, 32]. Even though IL-10 production appears to define all suppressive B cells identified thus far, including the B220+CD19+CD11c– population we reported [31], IL-10-producing B cells are not necessarily regulatory [49]. In fact, IL-10 expression may be transient as Bregs seem to transition through an IL-10-expressing phase to finally rest as immunoglobulin-secreting cells that might not rely on IL-10 for suppressive ability [50]. In our clinical trial [31], we discovered that the suppressive B cell population whose frequency was increased in cDC and iDC recipients did not rely on IL-10 for suppression in vitro [31]. Those reported B cells represent a heterogeneous population. Herein, we confirm that the bulk of suppressive activity inside those B cells is concentrated selleck screening library inside the already characterized CD19+CD24+CD38+ B cell population [32] which constitutes about 20% of the CD19+B220+CD11c– IL-10+ population, on average, in a small sample of normal individuals.

We also discovered that CD19+CD24+ cells are as suppressive as the Bregs reported by Mauri and colleagues [32, 40]. These cells could represent either a novel and distinct suppressive cell type, a less-differentiated population from which the CD19+CD24+/intermediateCD38+/intermediate B cells emerge under currently unknown conditions, or a phenotypically metastable population that modulates between CD27+/CD38+ and CD27–/CD38– states without any functional difference. Whether the increase

in frequency of the suppressive CD19+B220+CD11c– IL-10+ B cells in tolerogenic DC recipients as reported in [31] represents an effect of DC on B cells to induce the differentiation of suppressor precursors to become CD19+CD24+ suppressive cells, or to specifically induce the proliferation of pre-existing suppressive CD19+CD24+ cells with a plasticity in CD27 and CD38 www.selleck.co.jp/products/Temsirolimus.html expression, is currently unknown. Nevertheless, in view of our data, if RA is one of the mediators of DC effects on the generation of Bregs, both proliferation of existing Bregs and differentiation of precursors could be operational. DC generated from PBMC progenitors in the presence of GM-CSF/IL-4 are known to be tolerogenic [51, 52] and produce RA [53]. Mechanistically, evidence suggests that RA alone, as well as DC producing RA, maintain the balance of T cells in favour of immunosuppressive forkhead box protein 3 (FoxP3)+ Tregs at the expense of proinflammatory T helper 17 (Th17) T cells [54, 55].