Aryl hydrocarbon receptor-mediated perturbations in gene expression during early stages of CD4(+) T-cell differentiation

作者：Rohlman Diana; Pham Duy; Yu Zhen; Steppan Linda B; Kerkvliet Nancy I^*

来源：Frontiers in Immunology, 2012, 3: 223.

DOI：10.3389/fimmu.2012.00223

• aryl hydrocarbon receptor
• 2,3,7,8-tetrachlorodibenzo-p-dioxin
• CD4(+) T-cell differentiation
• gene expression
• IL-22

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 CD/L 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 n M 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 underTh17 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 ll22 that was seen under all culture conditions. Independent of TCDD, AhR down-regulated the expression of ll77a 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.

• 出版日期2012