APRIL Induces a Novel Subset of IgA+ Regulatory B Cells That Suppress Inflammation via Expression of IL-10 and PD-L1.

Cynthia M Fehres,Nataliya G Yeremenko,Michael Hahne,Gabriela Franco Salinas,Dominique L P Baeten,Bertrand Huard,Nathalie O Van Uden,Leticia Fernandez,Hergen Spits,Leonie M Van Duivenvoorde,Jacques Morel

doi:10.3389/fimmu.2019.01368

Abstract

Regulatory B cells (Bregs) are immunosuppressive cells that modulate immune responses through multiple mechanisms. The signals required for the differentiation and activation of these cells remain still poorly understood. We have already shown that overexpression of A PRoliferation-Inducing Ligand (APRIL) reduces the incidence and severity of collagen-induced arthritis (CIA) in mice. Furthermore, we have described that APRIL, but not BAFF, promoted IL-10 production and regulatory functions in human B cells. Therefore, we hypothesized that APRIL, but not BAFF, may be involved in the induction and/or activation of IL-10 producing Bregs that suppress inflammatory responses in vitro and in vivo. Here, we describe that APRIL promotes the differentiation of naïve human B cells to IL-10-producing IgA+ B cells. These APRIL-induced IgA+ B cells display a Breg phenotype and inhibit T cell and macrophage responses through IL-10 and PD-L1. Moreover, APRIL-induced IL-10 producing Bregs suppress inflammation in vivo in experimental autoimmune encephalitis (EAE) and contact hypersensitivity (CHS) models. Finally, we showed a strong correlation between APRIL and IL-10 in the inflamed synovial tissue of inflammatory arthritis patients. Collectively, these observations indicate the potential relevance of this novel APRIL-induced IgA+ Breg population for immune homeostasis and immunopathology.

Highlights

Over the past decade, Bregs have emerged as a novel subset of cells implicated in the inhibition of excessive inflammation
As A PRoliferation-Inducing Ligand (APRIL) is known to induce IgA class switching [37,38,39], we started to investigate our hypothesis that APRIL drives IL-10-producing Breg cells [27] by assessing if human IgA+ B cells had an increased potential to produce IL10 compared to other B cell subsets
The IgA+ B cell clones produced even without PMA/IO stimulation significantly higher levels of IL-10 compared to the other types of B cells clones: on average the IgA+ B cell clones produced 142 pg/ml of IL-10 vs. 24 pg/ml (p = 0.026), 4 pg/ml (p = 0.003), and 2 pg/ml (p = 0.003) of IL-10 produced by the naïve, IgM and IgG B cell clones, respectively

Summary

Introduction

Bregs have emerged as a novel subset of cells implicated in the inhibition of excessive inflammation. In contrast to the well-described regulatory functions of Bregs, the phenotypical and molecular identity of these cells is still not fully elucidated. IL-10 producing Bregs comprise subsets expressing CD1d, such as CD1dhiCD5−B220lowCD11b+IgM+ [3], CD1dhiCD5+ [10], and CD1dhiTIM+CD5+ [11] B cells. Peritoneal CD5+ B1 cells have been described as potent IL-10 producing Bregs, as well as CD21hiCD23hiCD24hi transitional type 2 marginal zone precursors [12], CD138+ plasmablasts [13], and IgA+ plasmocytes [14, 15]. Less is known about human Bregs, they have been reported within subsets of CD19+CD24hiCD38hiCD1d+ transitional B cells [6], CD24hiCD27+ B cells [16], and CD24−CD27hiCD38hi plasmablasts [7]. The signals required for this differentiation and activation of murine and/or human Bregs remain still poorly understood

Methods

Results

Conclusion