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.
Highlights
Aryl hydrocarbon receptor (AHR) is a prototypical xenobiotic sensing receptor/transcription factor that has been extensively studied in the context of toxicological responses to environmental chemical exposure [1, 2]
Given that CD5+ innate-like’ B cells (ILBs) express lymphocyte-specific protein tyrosine kinase (LCK) and LCK was differentially regulated by TCDD treatment, we hypothesized that the frequency of CD5+ B cells in peripheral blood could be predictive of relative sensitivity for any given individual to immunoglobulin M (IgM) suppression by TCDD
When the frequency of CD5+ CD19+ B cells is plotted against the respective suppression of IgM by TCDD in any given donor, we observe a strong, significant, positive correlation between the frequency of CD5 expression and the magnitude of IgM suppression elicited by TCDD treatment compared to Veh control (Figure 1B)
Summary
Aryl hydrocarbon receptor (AHR) is a prototypical xenobiotic sensing receptor/transcription factor that has been extensively studied in the context of toxicological responses to environmental chemical exposure [1, 2]. In the last decade, research into the biological roles of the AHR in the absence of xenobiotic exposure has increased markedly. Despite the abundance of research on the AHR in other immune cell subsets, the AHR has historically been studied in the context of immunotoxicology with B cells representing one of the most sensitive immunological targets of xenobiotic-mediated AHR activation as evidenced by suppression of B cell activation and secretion of immunoglobulins (Ig) [1]. CD5 is an immune inhibitory receptor that dampens signaling through the antigen receptor [12, 13] While it is primarily expressed by T cells, subsets of B cells express CD5 [9,10,11,12,13]. We hypothesized that CD5+ ILB could be selectively sensitive to AHR-mediated impairment
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