Abstract
SummaryRegulatory B cells (Bregs) play a critical role in the control of autoimmunity and inflammation. IL-10 production is the hallmark for the identification of Bregs. However, the molecular determinants that regulate the transcription of IL-10 and control the Breg developmental program remain unknown. Here, we demonstrate that aryl hydrocarbon receptor (AhR) regulates the differentiation and function of IL-10-producing CD19+CD21hiCD24hiBregs and limits their differentiation into B cells that contribute to inflammation. Chromatin profiling and transcriptome analyses show that loss of AhR in B cells reduces expression of IL-10 by skewing the differentiation of CD19+CD21hiCD24hiB cells into a pro-inflammatory program, under Breg-inducing conditions. B cell AhR-deficient mice develop exacerbated arthritis, show significant reductions in IL-10-producing Bregs and regulatory T cells, and show an increase in T helper (Th) 1 and Th17 cells compared with B cell AhR-sufficient mice. Thus, we identify AhR as a relevant contributor to the transcriptional regulation of Breg differentiation.
Highlights
B cells with immunosuppressive capacity, known as regulatory B cells (Bregs), play an important role in restraining inflammation
IL-10+ Bregs Present a Restricted Cytokine and Chemokine Gene Expression Profile To identify candidate genes that regulate the transcription of IL-10 in Bregs, arthritis was induced in IL-10eGFP reporter mice (Vert-x) (Madan et al, 2009)
Very few IL-10-producing Bregs were present in the joint or draining lymph nodes (DLNs) of arthritic mice (Figure S1A). This sorting strategy was chosen to capture the majority of described Breg subsets, including IL-10+type 2 marginal zone precursors (T2-MZPs), IL-10+marginal zone (MZ), and IL-10+CD1dhiCD5+, which have been shown to exert suppressive capacity via IL-10 in this model of arthritis and in other models of autoimmunity (Brummel and Lenert, 2005; Evans et al, 2007; Tian et al, 2001; Yanaba et al, 2009)
Summary
B cells with immunosuppressive capacity, known as regulatory B cells (Bregs), play an important role in restraining inflammation. Bregs suppress inflammatory cytokine production by T cells and promote the differentiation of Foxp3+ regulatory T cells (Tregs), primarily via the secretion of interleukin-10 (IL-10) (Carter et al, 2011; Rosser et al, 2014). In turn, suppress inflammatory cytokine production by T cells and promote the differentiation of Foxp3+ regulatory T cells (Treg) (Carter et al, 2011; Oleinika et al, 2018; Rosser et al, 2014)
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