Abstract
The aryl hydrocarbon receptor (AhR) has been shown to be required for optimal Thelper (Th) 17 cell activation. Th17 cells provide immunity against extracellular pathogens and are implicated in autoimmune diseases. Herein, the role of the AhR in cytokine production by Th17, and by the analogous population of T cytotoxic (Tc)17 cells, has been examined. Lymph node Tc (CD8+) and Th (CD4+) cells were isolated by negative selection from naive AhR+/− and AhR−/− mice and polarised to Tc1/Th1 or Tc17/Th17 phenotypes with appropriate cytokines. Cell differentiation was assessed as a function of mRNA and protein (ELISA and flow cytometry) expression for interferon (IFN)-γ and for key Th17 cytokines. In AhR+/− mice, Th17 cells displayed an exclusive IL-17 profile, which was markedly inhibited by a selective AhR antagonist to levels observed in AhR knockout mice. Addition of the natural AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) markedly enhanced Th17 cell activity in the heterozygotes. In contrast, Tc17 cells polarised into 3 distinct subsets: producing either IL-17 or IFN-γ alone, or both cytokines. Blocking AhR was also detrimental to Tc17 development, with reduced responses recorded in AhR−/− mice and antagonist-mediated reduction of IL-17 expression in the heterozygotes. However, Tc17 cells were largely refractory to exogenous FICZ, presumably because Tc17 cells express baseline AhR mRNA, but unlike Th17 cells, there is no marked up-regulation during polarisation. Thus, Th17 cell development is more dependent upon AhR activation than is Tc17 cell development, suggesting that endogenous AhR ligands play a much greater role in driving Th17 cell responses.
Highlights
An important property of adaptive immune function is the orchestration of polarised immune responses by the generation of discrete populations of CD4+ T helper (Th) and CD8+ cytotoxic T (Tc) lymphocytes [1,2]
The population that was most susceptible to the addition of the aryl hydrocarbon receptor (AhR) ligands was the IL-17/IFN-c fraction, where a,50% reduction was observed following addition of the antagonist but the agonist was without effect (Figure 1C, G)
In the investigations described here, dual strategies have been employed to characterise the role played by AhR in the regulation of Tc17 cell development
Summary
An important property of adaptive immune function is the orchestration of polarised immune responses by the generation of discrete populations of CD4+ T helper (Th) and CD8+ cytotoxic T (Tc) lymphocytes [1,2]. A more recent addition to known subsets of CD4+ Th cells are Th17 cells that have a characteristic cytokine secretion profile that includes IL-17A, IL-17F, IL-21 and IL-22. These cells play important roles in protective immunity and have been implicated in the pathogenesis of certain autoimmune diseases including multiple sclerosis, psoriasis, rheumatoid arthritis and Crohn’s disease [3,4,5]. Th17 cytokines are thought to enhance inflammation by paracrine induction of other proinflammatory factors, such as tumour necrosis factor-a and IL-6 [8,9]
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