IL‐10‐producing B cells are characterized by a specific methylation signature

Tonon, Silvia; Mion, Francesca; Dong, Jun; Chang, Hyun Dong; Dalla, Emiliano; Scapini, Patrizia; Perruolo, Giuseppe; Zanello, Andrea; Dugo, Matteo; Cassatella, Marco A.; Colombo, Mario P.; Radbruch, Andreas; Tripodo, Claudio; Pucillo, Carlo

doi:10.1002/eji.201848025

Cited by 19 publications

(11 citation statements)

References 28 publications

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“…Since our analysis, Tonon et al. identified 142 differentially expressed genes in sorted IL‐10 producing B cells stimulated during 5 hours with LPS, PMA, and ionomycin [44]. Interestingly, some important genes such as Il10, Lag3, Cd70 , and Ctla4 were also present in this dataset, confirming our strategy.…”

Section: Discussionsupporting

confidence: 74%

Transcriptional meta‐analysis of regulatory B cells

et al. 2020

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Regulatory B cells (Bregs) have the ability to regulate inflammation in various pathological situations, making them key players in immune regulation. Several mechanisms have been described and we recently identified a GZMB expressing Breg population in kidney transplanted patients who tolerate a kidney graft. To further investigate their biology and mechanisms, we conducted a transcriptomic analysis by RNAseq of these cells and we performed the first weighted meta‐analysis of publicly available transcriptomic data from published Breg studies both in humans and mice. We identified two distinct and unique transcriptional signatures of 126 and 93 genes, respectively, associated with these Bregs. While we highlighted genes coding for proteins with potent involvement in regulatory functions, proliferation, and coding for transcription factors, the comparison between humans and mice did not allow identifying a common pattern. Thus, our results suggest distinct species‐restricted Breg transcriptional signatures in humans and mice.

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Section: Discussionsupporting

confidence: 74%

Transcriptional meta‐analysis of regulatory B cells

et al. 2020

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“…Despite extensive research into the epigenetic regulation of IL-10 expression in immune cells, there is still a paucity of studies on B cells ( 169 , 170 ). Recent work explored the DNA methylation signature of the il10 locus in B cells and defined “early” and “delayed il10 regulatory regions,” which are demethylated, or accessible, in B cells that produce IL-10 after short- or long-term stimulation with LPS, respectively ( 171 ). These results are even more meaningful considering that the “delayed il10 regulatory region” is a binding site for IRF4 in IL-10 + plasmablasts, where it might interact with NFATc1 to promote IL-10 expression ( 55 ).…”

Section: Regulation Of Il-10 Expression By B Cellsmentioning

confidence: 99%

Immunosuppressive Mechanisms of Regulatory B Cells

et al. 2021

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Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

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“…6C). Apart from Th cells, B cells could secret cytokines that had antibody‐independent functions of B cells [32‐34]. We also found that the levels of IL‐6, IL‐10, TNF‐α, IFNγ, IL‐12, IL‐4, and IL‐17A in the supernatant from LPS‐stimulated Itch −/− B cells were significantly increased (Fig.…”

Section: Discussionmentioning

confidence: 76%

The E3 ubiquitin ligase Itch deficiency promotes antigen‐driven B‐cell responses in mice

Fang

Zhai

et al. 2020

Eur J Immunol

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Deficiency of Itch, an E3 ubiquitin ligase, usually induced severe systemic and progressive autoimmune disease. The Itch function is well studied in T cells but not in B cells. We hypothesize that B‐cell‐specific Itch deficiency promoted antigen‐induced B‐cell activation and antibody‐expressing plasma cell (PC) production. We found that unlike Itch KO, Itch cKO (CD19creItchf/f) mice did not demonstrated a significant increase in the sizes of spleens and LNs, antibody level, and base mutation of antibody gene. However, in line with the fact that Itch expression decreased in GC B cells, PCs, and plasmablast (PB)‐like SP 2/0 cells, Itch deficiency promoted B‐cell activation and antibody production induced by antigens including lipopolysaccharide (LPS) and sheep red blood cells (SRBCs). Mechanistically, we found that Itch deficiency promotes antigen‐induced cytokine production because Itch controls the proteins (e.g., eIF3a, eIF3c, eIF3h) with translation initiation factor activity. Altogether, our data suggest that Itch deficiency promotes antigen‐driven B‐cell response. This may provide hints for Itch‐targeted treatment of patients with autoimmune disease.

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IL‐10‐producing B cells are characterized by a specific methylation signature

Cited by 19 publications

References 28 publications

Transcriptional meta‐analysis of regulatory B cells

Transcriptional meta‐analysis of regulatory B cells

Immunosuppressive Mechanisms of Regulatory B Cells

The E3 ubiquitin ligase Itch deficiency promotes antigen‐driven B‐cell responses in mice

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