Aryl hydrocarbon receptor as an intrinsic novel checkpoint that inhibits TLR7-induced B-cell activation in lupus 2500

Abstract Description Systemic lupus erythematosus (SLE) is marked by an increase in T-bet+CXCR3+Fcrl5+IgD−CD27− double negative 2 (DN2) B cells, driven by heightened TLR7 signaling. We found that SLE patients have reduced aryl hydrocarbon receptor (AhR) expression in naïve and DN B cells compared to healthy controls, along with lower expression of the AhR target gene, Cyp1a1. To investigate the role of AhR in B cell differentiation, we studied B cells from B-cell-specific AhR knockout mice (AhRf/f x Cd19.Crehet: AhR B-KO) and wild-type (AhR+/+ x Cd19.Crehet: AhR B-WT) controls. In vivo administration of mice with R848, a TLR7 ligand, showed an increase in Fcrl5+T-bet+ B cells in both the follicular (p = 0.018) and marginal zone (p = 0.014) subsets in AhR B-KO, compared to AhR B-WT mice. AhR deficiency in B cells also led to a rise in CD80+CXCR3+ populations at IgD + (p = 0.005) and IgD−IgM − (p = 0.023) stages. In vivo treatment of R848-injected BXD2 mice with kynurenine (Kyn), a natural agonistic ligand of AhR, significantly reduced CD11c+Ki67+CD138+ plasma B cells (p = 0.0112) and CD11c+T-bet+ B cells in the germinal center (p = 0.025). These findings suggest that impaired AhR signaling may drive abnormal activation and DN2 B cell development in SLE. In addition, our results highlight the potential of activating AhR with natural ligands such as Kyn to inhibit autoreactive B cell development in SLE. Funding Sources VA Merit Review grant (1I01BX006099) and NIH R01 AI134023 to J.D.M. Topic Categories Basic Autoimmunity (BA)