Mice Lacking Endogenous IL-10–Producing Regulatory B Cells Develop Exacerbated Disease and Present with an Increased Frequency of Th1/Th17 but a Decrease in Regulatory T Cells

Abstract

IL-10–producing B cells, also known as regulatory B cells (Bregs), play a key role in controlling autoimmunity. In this study, we report that chimeric mice specifically lacking IL-10–producing B cells (IL-10−/−B cell) developed an exacerbated arthritis compared with chimeric wild-type (WT) B cell mice. A significant decrease in the absolute numbers of Foxp3 regulatory T cells (Tregs), in their expression level of Foxp3, and a marked increase in inflammatory Th1 and Th17 cells were detected in IL-10−/− B cell mice compared with WT B cell mice. Reconstitution of arthritic B cell deficient (μMT) mice with different B cell subsets revealed that the ability to modulate Treg frequencies in vivo is exclusively restricted to transitional 2 marginal zone precursor Bregs. Moreover, transfer of WT transitional 2 marginal zone precursor Bregs to arthritic IL-10−/− mice increased Foxp3+ Tregs and reduced Th1 and Th17 cell frequencies to levels measured in arthritic WT mice and inhibited inflammation. In vitro, IL-10+/+ B cells established longer contact times with arthritogenic CD4+CD25− T cells compared with IL-10−/− B cells in response to Ag stimulation, and using the same culture conditions, we observed upregulation of Foxp3 on CD4+ T cells. Thus, IL-10–producing B cells restrain inflammation by promoting differentiation of immunoregulatory over proinflammatory T cells.

Imbalance of different types of CD4+forkhead box protein 3 (FoxP3)+ T cells in patients with new-onset systemic lupus erythematosus

“…IL-10 is an inhibitory cytokine, and lower levels of serum Il-10 are detected in mouse models of SLE [31][32][33]. Therefore, our findings support the notion that CD4…”

Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

“…Bregs were shown to have a protective effect in autoimmune disease models of experimental autoimmune encephalomyelitis and CIA (45,46). Also, human bone marrow MSCs were shown to upregulate Bregs in an experimental autoimmune encephalomyelitis model (47).…”

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

“…First, B cells produce a proinflammatory cytokine profile. Identification of decreased B-cell IL-10 in obesity justifies future studies that will test the possibility that IL-10 + B cells play critical roles in metabolic disease etiology, as shown for other Th1/Th17-mediated diseases (3,4,(27)(28)(29). Second, B cells support a disease-associated proinflammatory T-cell ratio as shown by both in vivo and in vitro mouse studies, complemented by ex vivo human immune cell analyses.…”

“…We showed B cells from T2D subjects secrete a proinflammatory cytokine profile, including an extraordinary inability to secrete the potent anti-inflammatory cytokine IL-10 and an elevated production of proinflammatory IL-8 compared with B cells from non-T2D subjects (2). Given the importance of B-cell IL-10 in preventing numerous inflammatory diseases (3,4) and the links between IL-8 and T2D (5,6), these data suggest that altered B-cell cytokine production plays an important role in initiating or promoting IR/T2D. Published analyses further support a role for B cells in IR and include studies of B cell-null New Zealand Obese (NZO) mice, which, in contrast to B cell-sufficient NZOs, fail to develop IR in response to obesity (7).…”