LAUSR

Over the last several years, the aryl hydrocarbon receptor (AHR) has gone from being characterized as not only a receptor that modulates cellular responses to myriad external environmental changes but also as one that regulates intricate aspects of immune homeostasis in response to endogenously produced ligands. Indeed, several endogenous AHR ligands have now been identified, including chemicals derived from tryptophan, phytochemicals, or commensal microbiota.1,2 Although AHR might play many roles, no doubt it remains a critical receptor in modulating immune responses within the context of exposure to environmental chemicals. In this issue of Environmental Health Perspectives, Liu et al. provide a detailed characterization of immune effects of fine particulate matter [PM with an aerodynamic diameter of ≤2:5 lm (PM2:5)] obtained from atmospheric monitoring stations in Taiwan.3 This PM2:5 contained various polycyclic aromatic hydrocarbons (PAHs), including indeno[1,2,3-cd]pyrene (IP).4 They observed that intratracheal administration of PM2:5 or IP alone exacerbated pathology and modulated immune responses by using a mouse model for house dust mite (HDM)-mediated asthma.3 Importantly, they used mass cytometry to determine that both PM2:5 and IP exposure increased the percentage and number of TCRbCD4+CXCR5+Bcl-6+PD-1hi T follicular helper (Tfh) cells in the lung-draining lymph nodes. In addition, the enhancement in Tfh cells was dependent on AHR expression in T cells, at least for PM2:5. Tfh cells are CD4+ T cells that play a critical role in inducing isotype-switched antibody responses in germinal centers (GCs).5 Therefore, it was important that they also demonstrated that IP enhanced levels of HDM-specific immunoglobulin E (IgE) and IgG in serum.3 Previously, they had demonstrated that IPmediated exacerbation in a mouse ovalbumin-induced model of allergic lung inflammation was attenuated with the AHR antagonist CH223191.4 Interestingly, the observation that IP, as an AHR ligand, increased the percentage and number of Tfh cells contradicts another recent paper, in which other AHR ligands suppressed Tfh cell percentage and number in mice infected with influenza A virus.6 In that paper, the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the tryptophan derivative 2-(10Hindole-30-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), and the endogenous ligand kynurenic acid (KYNA) all suppressed CD4+CD44+CXCR5PD-1hi Tfh in infected mice.6 Using TCDD, Houser and Lawrence also showed in lung-draining lymph nodes that AHR activation significantly suppressed Tfh cell number as early as day 3 postinfection, that the GC B cell number directly correlated with Tfh cell number and, further, that AHR activation suppressed GC B cells. Consistent with these findings, AHR activation with ligands, including TCDD and ITE, also reduced virus-specific IgG levels in plasma.6 The juxtaposition of the results from these papers displays a common theme in the AHR field: Different AHR ligands produce different, and sometimes opposite, effects in the immune system (Figure 1). The reasons for this remain uncertain, but they could be due to ligand affinity, ligand bioavailability or metabolism, strength of response, or differences in the immune stimulus. Indeed, the two juxtaposed studies used different disease models, with Houser and Lawrence6 using a replicating pathogen (influenza virus), and Liu et al.3 using a representative allergen (HDM). However, even in the same model system, two different AHR ligands can produce opposite effects. For instance, during influenza A virus infection in which TCDD suppressed Tfh cell