Aryl Hydrocarbon Receptor-Mediated Perturbations in Gene Expression during Early Stages of CD4(+) T-cell Differentiation.

Abstract:

:Activation of the aryl hydrocarbon receptor (AhR) by its prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mediates potent suppression of T-cell dependent immune responses. The suppressive effects of TCDD occur early during CD4(+) T-cell differentiation in the absence of effects on proliferation and have recently been associated with the induction of AhR-dependent regulatory T-cells (Treg). Since AhR functions as a ligand-activated transcription factor, changes in gene expression induced by TCDD during the early stages of CD4(+) T-cell differentiation are likely to reflect fundamental mechanisms of AhR action. A custom panel of genes associated with T-cell differentiation was used to query changes in gene expression induced by exposure to 1 nM TCDD. CD4(+) T-cells from AhR(+/+) and AhR(-/-) mice were cultured with cytokines known to polarize the differentiation of T-cells to various effector lineages. Treatment with TCDD induced the expression of Cyp1a1, Cyp1b1, and Ahrr in CD4(+) T-cells from AhR(+/+) mice under all culture conditions, validating the presence and activation of AhR in these cells. The highest levels of AhR activation occurred under Th17 conditions at 24 h and Tr1 conditions at 48 h. Unexpectedly, expression levels of most genes associated with early T-cell differentiation were unaltered by AhR activation, including lineage-specific genes that drive CD4(+) T-cell polarization. The major exception was AhR-dependent up-regulation of Il22 that was seen under all culture conditions. Independent of TCDD, AhR down-regulated the expression of Il17a and Rorc based on increased expression of these genes in AhR-deficient cells across culture conditions. These findings are consistent with a role for AhR in down-regulation of inflammatory immune responses and implicate IL-22 as a potential contributor to the immunosuppressive effects of TCDD.

journal_name

Front Immunol

journal_title

Frontiers in immunology

authors

Rohlman D,Pham D,Yu Z,Steppan LB,Kerkvliet NI

doi

10.3389/fimmu.2012.00223

subject

Has Abstract

pub_date

2012-08-06 00:00:00

pages

223

issn

1664-3224

journal_volume

3

pub_type

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