The aryl hydrocarbon receptor (AhR) ligand VAF347 selectively acts on monocytes and naïve CD4+ Th cells to promote the development of IL-22-secreting Th cells
Introduction
Naïve CD4+ T cells differentiate into heterogeneous effector Th cell populations that can be classified according to their cytokine production profile. The different Th cell subsets express characteristic transcription factors which are required for the differentiation process and to exert their effector functions [1]. Th1 cell polarization is promoted by IL-12 and requires T-bet, Th2 cell differentiation is induced by IL-4 and depends on GATA-3 and Th17 cells are generated following simultaneous signaling with TGF-β and the inflammatory cytokines IL-1 and IL-6 under the control of the transcription factors RORC2 and ROR-α. IL-22, a member of the IL-10 family, is generally produced by cells which also secrete IL-17 and therefore it has been often considered as an effector cytokine product of Th17 cells. Indeed, IL-17 and IL-22 expression is often correlated with inflammatory processes, such as those occurring in the affected intestinal tract and skin of patients suffering Crohn’s disease and psoriasis, respectively [2], [3], [4], [5]. However, the development of Th22 cells, producing IL-22 in the absence of IL-17 [6], [7], can be selectively induced by combination of IL-6 and TNF-α or facilitated by stimulation of naïve Th cells with Langerhans cells and plasmacytoid dendritic cells. Furthermore, IL-22 is also expressed by cell-types, such as NKp46+ cells, that do not secrete IL-17 [8], [9]. Th17 cells contribute to host defense against extracellular pathogens at mucosal sites and are also implicated in the development of autoimmune diseases. In these situations, IL-17 seems to play a major inflammatory role, whereas IL-22 has been rather implicated in tissue-repair and wound-healing processes, particularly in skin and liver tissue [2]. Together, these observations would suggest a differential regulatory requirement for the production of IL-17 and IL-22.
The transcription factor AhR (AHR; A000229) has been historically linked to xenobiotic responses to environmental factors, but recently it has been implicated in regulatory processes controlling homeostatic and inflammatory immune responses. AhR interacts with several ligands that include xenobiotics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCCD), tryptophan metabolites such as 6-formylin-dolo[3,2b-] carbazole (FICZ) and synthetic chemicals such as VAF347 [10]. The low molecular weight compound VAF347 and its pro-drug VAG539, were identified as AhR agonists with potent anti-inflammatory activities [11]. In vivo, VAG539 suppresses lung inflammation in a murine model of experimental asthma and promotes long term allograft acceptance in pancreatic islet transplantation model. These effects were attributed to altered dendritic cell (DC) functions. Consequently, VAF347 has been shown to promote the in vitro differentiation of tolerogenic-like DCs from mouse bone marrow and to suppress the production of IL-6 by monocyte derived DC (Mo-DCs) [12], [13].
AhR regulates the differentiation of IL-22 producing Th cells [14]. CD4+ T cells from AhR-deficient mice fail to produce IL-22 when exposed to AhR ligands, while they still develop normal Th17 cell responses [14]. However, retroviral transduction of AhR, alone or in combination with RORC2, is not sufficient to induce IL-22. These results indicate the necessity of AhR to interact with other transcriptional factors, that may include Stat5 and Stat1, to exert its regulatory effects and therefore it is unlikely that AhR represents the exclusive master transcription factor required for Th22 cell development [10], [14], [15], [16]. A recent report suggests that the regulation by AhR agonists may be species-specific [17]. FICZ decreases human Th17 cell development and favors human IL-22 expression while in the mouse, it promotes both IL-17 and IL-22 production [14], [15], [16], [17].
AhR transcripts are expressed in human antigen presenting cells (APC) as well as on naïve and memory T cells [17], [18]. Here, we investigated whether AhR ligation by VAF347 on monocytes or T cells impacts on the IL-22 production. More precisely, we examined how VAF347 can indirectly or directly regulate IL-22, IL-17 and IFN-γ expression by differentiated or memory CD4+ Th cells.
Section snippets
Cell cultures
Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers in compliance with Institutional Ethic Committees: The Research Centre of the University of Montreal Hospital Centre (CRCHUM)) and the Swiss Red Cross Center, Basel.
Enriched-monocytes (EM) and monocyte-derived DCs (Mo-DCs) were prepared as described [19]. Briefly, EM were differentiated into DCs in the absence or presence of VAF347 (Mo-DCs or VAF-DCs, respectively, using 50 nM compound; Novartis Institutes for
AhR ligation by VAF347 on monocytes generates DCs (VAF-DCs) that instruct a naïve Th cell differentiation program which promotes IL-22 and inhibits IL-17 secretion
We have assessed the phenotype and function of DCs differentiated from CD14+ monocytes in the absence (Mo-DCs) or presence of VAF347 (VAF-DCs) compound. We found that the expression of CD86 and MHC class II molecules was decreased on VAF-DCs when compared to Mo-DCs (Fig. 1A). Down-regulation of costimulatory molecules and MHC class II was still observed on VAF-DCs following their activation with PGN in the absence of VAF347. Of note, VAF-DCs displayed residual CD14 expression, indicating that
Conflict of interest
J.C., L.K. and C.R. are working for the Novartis Institute of Biomedical Research, which is engaged in the development of medicine to treat among others, autoimmune diseases. N.B., M.R., M.W. and M.S. have no conflicting financial interests.
Acknowledgment
This work was supported by the Canadian Institute for Health and Research (CIHR Grant,) and grant in aid from Novartis Institute.
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