Identification of a Sensitive Human Immunological Target of Aryl Hydrocarbon Receptor Activation: CD5+ Innate-Like B Cells

Abstract

Xenobiotic-mediated activation of the aryl hydrocarbon receptor (AHR) is immunotoxic in a number of immune cell types, with the B cell being a well-established sensitive target. Recent advances have provided evidence that the B cell repertoire is a heterogeneous population, with subpopulations exhibiting vastly different cellular and functional phenotypes. Recent work from our laboratory identified the T cell specific kinase lck as being differentially regulated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent activator of AHR. While LCK is primarily expressed in T cells, a subset of CD5+ B cells also express LCK. CD5 positivity describes a broad class of B lymphocytes termed innate-like B cells (ILBs) that are critical mediators of innate immunity through constitutive secretion of polyvalent natural immunoglobulin M (IgM). We hypothesized that CD5+ ILBs may be sensitive to AHR-mediated immunotoxicity. Indeed, when CD5+ B cells were isolated from the CD19+ pool and treated with TCDD, they showed increased suppression of the CD40 ligand-induced IgM response compared to CD5- B cells. Further, characterization of the CD5+ population indicated increased basal expression of AHR, AHR repressor (AHRR), and cytochrome p450 family 1 member a1 (CYP1A1). Indeed the levels of AHR-mediated suppression of the IgM response from individual donors strongly correlated with the percentage of the B cell pool that was CD5+, suggesting that CD5+ B cells are more sensitive to AHR-mediated impairment. Together these data highlight the sensitive nature of CD5+ ILBs to AHR activation and provide insight into mechanisms associated with AHR activation in human B cells.

TCDD Inhibition of IgG1 Production in Experimental Autoimmune Encephalomyelitis (EAE) and In Vitro

“…However, the CD5+ cells also produced IgG1 and IgG3 in response to LPS + IL-4, so these CD5+ cells likely also play a role in immune defense [ 30 ]. Recently in human B cells, it was observed that TCDD modestly increased IgG in CD5- B cells in response to CD40L + IL-2 and IL-21 for 7 days [ 31 ].…”

Role of Programmed Cell Death Protein-1 and Lymphocyte Specific Protein Tyrosine Kinase in the Aryl Hydrocarbon Receptor- Mediated Impairment of the IgM Response in Human CD5+ Innate-Like B Cells

“…The binding of ligands to PD-1 initiates inhibitory signaling cascades that suppress immune responses on PD-1 expressing target cells. Interestingly, high basal expression of PD-1 has been reported in CD5 + ILBs ( 16 , 17 ). PD-1 signaling involves the phosphorylation of the immunoreceptor tyrosine switch motifs (ITSMs) and immunoreceptor tyrosine inhibitory motifs (ITIMs) ( 14 ).…”

“…While the underlying mechanism by which the AHR modulates antibody responses in B cells is still largely unknown, recent studies have demonstrated AHR activation induced LCK expression in human primary B cells and LCK is critical for optimal IgM secretion ( 52 ). Indeed, a recent report from Blevins and colleagues demonstrated that CD5 + ILB were preferentially sensitive to AHR-mediated suppression of IgM secretion ( 17 ). Moreover, AHR-mediated induction of LCK protein expression was limited to CD5 + ILB, further implicating a role for LCK in AHR-mediated suppression of IgM secretion ( 17 ).…”

“…Indeed, a recent report from Blevins and colleagues demonstrated that CD5 + ILB were preferentially sensitive to AHR-mediated suppression of IgM secretion ( 17 ). Moreover, AHR-mediated induction of LCK protein expression was limited to CD5 + ILB, further implicating a role for LCK in AHR-mediated suppression of IgM secretion ( 17 ). Consequently, Blevins et al.…”

“…Consequently, Blevins et al. also found that TCDD-treatment of human CD5 + ILB significantly enhanced PD-1 protein expression, providing a putative mechanism for AHR-mediated IgM suppression ( 17 ). Curiously, it has also been reported that treatment with exogenous IFNγ blocked AHR-mediated suppression of the IgM response in mouse splenocytes as well as human B cells ( 53 , 54 ).…”