Induction and Differentiation of IL-10–Producing Regulatory B Cells from Healthy Blood Donors and Rheumatoid Arthritis Patients

Abstract

The most important feature of B cells is the production of Abs upon activation; additionally, B cells produce pro- and anti-inflammatory cytokines in response to certain stimuli. IL-10-producing B cells represent a major subset of regulatory B cells (Bregs) that suppress autoimmune and inflammatory responses. B cells play a crucial role in the development and maintenance of the chronic inflammatory autoimmune disease rheumatoid arthritis (RA); however, controversial data are available on IL-10- producing Bregs in RA. Our aim was to identify the optimal conditions that induce IL-10 Bregs and, furthermore, to shed light on the signaling pathways that are responsible for their expansion. The results show that dual stimulation by CpG and CD40L for 48 h is optimal for IL-10 induction, and this can be synergistically boosted by IL-21. We identified the CD19CD27 memory B cell population as the major source of IL-10 Bregs. We detected significantly fewer CD19CD27IL-10 cells in RA patients compared with healthy controls, and these were functionally defective in suppressing IFN-γ production by CD4 T cells in coculture. IL-21 drastically increased the number of IL-10 Bregs within the CD19CD27 and CD19CD27 populations; furthermore, it induced the appearance of IL-10Blimp-1 plasmablasts. Monitoring the phosphorylation of key signaling molecules revealed that activation of ERK, p38, and CREB is indispensable for the induction of IL-10 production, whereas phosphorylation of STAT3 further enhances IL-10 expression in human Bregs. We conclude that CREB and STAT3 are the key transcription factors responsible for the expansion and differentiation of human IL-10-producing Bregs.

Altered frequency of CD24highCD38high transitional B cells in patients with cardiac involvement of chronic Chagas disease

“…In order to better characterize the phenotypic distribution of B10 cells in CCD patients, we assessed the frequency of B10 cells according to CD27 expression alone and in combination with CD24 and CD38. According to CD27 expression, B10 cells were mainly found in the CD27 + (memory) population in the non-infected group, as was previously reported in samples from healthy blood donors (27) and the same pattern was observed in CCD patients (Fig. 4B).…”

“…2D). Since CD24 high CD38 high transitional B cell population has been associated with IL-10mediated, regulatory B cell functions in autoimmune and infectious human diseases (11,26,27), we next studied IL-10 producing B cells (B10 cells) in peripheral blood from patients with the different clinical forms of CCD. Thus, we performed an intracellular flow cytometry on PBMC, after in vitro incubation with PMA and ionomicyn in the presence of the protein transport inhibitor Brefeldin A for 5 h. We assessed the frequency of total B10 cells and B10 cell subsets according to CD24, CD38 and CD27 expression (11,27) (Fig.…”

B cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis

“…However, most HIV-108 infected patients present with cryptococcal meningitis at a very advanced state of 109 immunosuppression with CD4+ T cell counts <50 cells/µL (1). 110 naïve T cell activation, generating and maintaining serological memory, and regulating 112 immune responses in health and in disease (3,4). In animal models, B cells produce 113 antibodies against the cryptococcal polysaccharide capsule and other fungal antigens 114 (5,6) that may attenuate infection and mediate fungal clearance (7).…”

MiR‐15a/16‐1 deficiency induces IL‐10‐producing CD19+ TIM‐1+ cells in tumor microenvironment

“…The engagement of BCR is thought to play a role in the early stage, whereas the activation of CD40 and Toll‐like receptors (TLRs) plays a role in the late stage of Breg cell differentiation. Several signalling proteins, such as Erk, p38, glycogen synthase kinase 3‐β (GSK3‐β), Smad, Signal transducers and activators of transcription (STATs), mammalian target of rapamycin (mTOR) and nuclear factor‐kappa B (NF‐κB), are involved in IL‐10 production …”

“…Several signalling proteins, such as Erk, p38, glycogen synthase kinase 3-β (GSK3-β), Smad, Signal transducers and activators of transcription (STATs), mammalian target of rapamycin (mTOR) and nuclear factor-kappa B (NF-κB), are involved in IL-10 production. [9][10][11] The miR-15a/16 gene complex is located in the intron of the DLEU2 gene in the human 13q14 region, which is recognized as a tumour-suppressor gene. 12 The deletion of this gene region is closely related not only with chronic B lymphocytic leukaemia, but also with various solid tumours such as melanoma, colorectal cancer, prostate cancer, breast cancer and bladder cancer.…”