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Aryl hydrocarbon receptor (AhR) ligation by VAF347 promotes Th22 and inhibits Th1 polarization.

Baba, Nobuyasu and Rubio, Manuel and Kenins, Linda and Regairaz, Camille and Woisetchlager, Maximilian and Carballido, Jose and Sarfati, Marika (2012) Aryl hydrocarbon receptor (AhR) ligation by VAF347 promotes Th22 and inhibits Th1 polarization. Human Immunology, 73. pp. 795-800. ISSN 0198-8859

Abstract

The Aryl hydrocarbon receptor (AhR) is a transcription factor implicated in human and murine Th22 polarization, which does not notably influence the expression of IL-17 in mice. The low molecular weight compound VAF347, and its pro-drug version VAG539, interact with AhR and modulate dendritic cell (DC) function. Here we show that phenotypic differentiation of human monocytes into DC was altered in the presence of VAF347 (VAF-DC). The effects of VAF347 extended to the cytokine secretion pattern of DC, particularly those required for Th17/Th22 differentiation of naïve T cells. VAF-DC instructed naïve CD4+ T cells to suppress their Th17 program while promoting IL-22 secretion. VAF347 facilitated IL-1-induced polarization of purified naïve T cells into single IL-22+ and double IL-22+IL-17+ cells. Enhanced Th22 differentiation correlated with suppression of Th1 development that included IL-22+IFN-+ and IL-17+IFN-+ cells. Furthermore, the production of IL-17 by memory Th17/Th22 cells seems to be more plastic than the corresponding production of IL-22, which on memory cells is less amenable to regulation by AhR modulators or gene silencing. Collectively, IL-17 and IL-22 are differentially regulated by VAF347, which enhances IL-22 and reduces IFN- expression. IL-17 and IFN- favor autoimmunity, while IL-22 appears essential in epithelial barrier integrity suggesting that the manipulation of AhR may be advantageous for the host to reduce inflammation and preserve an IL-22-mediated protective function.

Item Type: Article
Keywords: Th22, AhR, human Th cell differentiation
Date Deposited: 12 Nov 2015 00:45
Last Modified: 12 Nov 2015 00:45
URI: https://oak.novartis.com/id/eprint/4842

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