The Aryl Hydrocarbon Receptor Promotes IL-10 Production by NK Cells

Abstract

The cytokine IL-10 has an important role in limiting inflammation in many settings, including toxoplasmosis. In these studies, an IL-10 reporter mouse was used to identify the sources of this cytokine following challenge with Toxoplasma gondii. During infection, multiple cell types expressed the IL-10 reporter but natural killer cells were a major early source of this cytokine. These IL-10 reporter+ NK cells expressed high levels of the IL-12 target genes T-bet, KLRG1, and IFN-γ, and IL-12 depletion abrogated reporter expression. However, IL-12 signaling alone was not sufficient to promote NK cell IL-10 and activation of the aryl hydrocarbon receptor (AHR) was also required for maximal IL-10 production. NK cells basally expressed the AHR, relevant chaperone proteins, and the AHR nuclear translocator (ARNT), which heterodimerizes with the AHR to form a competent transcription factor. In vitro studies revealed that IL-12 stimulation increased NK cell AHR levels, and the AHR and ARNT were required for optimal production of IL-10. Additionally, NK cells isolated from T. gondii-infected Ahr-/- mice had impaired expression of IL-10, which was associated with increased resistance to this infection. Together, these data identify the AHR as a critical cofactor involved in NK cell production of IL-10.

The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

“…Importantly, we found that expression levels of IL-10, which is a regulatory hallmark cytokine of some subpopulations of Treg cells but is also expressed by macrophages, Th2, and natural killer cells, were reduced at 15 dpi in AhR KO mice, consistently with the previously reported function of AhR as a positive regulator of the IL-10 promoter (49). These data suggest that one of the mechanisms that result in suppression of inflammation by activated AhR during T. cruzi infection is mediated by IL-10 transcriptional regulation.…”

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…For instance, Th17 cells need AhR activation for IL-22 secretion, and the immunoglobulin locus can be suppressed by TCDD in an AhR-dependent fashion Sulentic and Kaminski, 2011;Quintana and Sherr, 2013). Natural killer (NK) cells express AhR at moderate levels, and AhR activation stimulates antitumor activity as well as resistance to infections (Wagage et al, 2014). However, the examples of naïve B cells or NK cells suggest caution on simplifying projections such as, "AhR is only relevant when expressed in higher amounts."…”

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…The induced manipulation toward the Th2 profile assures increased surviving possibility for different infective agents, such as viruses, chlamydias, and parasites [65, 67-69, 73,74,[77][78][79]. The early IL-10 production by T cell, B cell, and monocyte/macrophage (but not on NK and DC) activation can lead to chronicity of lymphocytic choriomeningitis and B hepatitis virus infections, and the IL-10-mediated early T cell Similarly to viral infections, parasite-induced IL-10 production by various immune cells is associated with impaired resistance to protozoan and nematodes [80,81,86,87]. However, experiments with Leishmania major in mice have demonstrated that the additional Th2 cytokines deficiency and increased IL-10 production on DCs may lead to rapid disease progression and increased parasites' survival due to reduced killing effector functions [87].…”