HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Related articles in The JI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Marshall, N. B. Articles by Kerkvliet, N. I. Search for Related Content PubMed PubMed Citation Articles by Marshall, N. B. Articles by Kerkvliet, N. I.

Functional Characterization and Gene Expression Analysis of CD4⁺CD25⁺ Regulatory T Cells Generated in Mice Treated with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin¹

Nikki B. Marshall^*, William R. Vorachek, Linda B. Steppan, Dan V. Mourich^* and Nancy I. Kerkvliet^2,,

^* Department of Microbiology, Department of Environmental and Molecular Toxicology, and Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331

Although the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are mediated through binding and activation of the aryl hydrocarbon receptor (AhR), the subsequent biochemical and molecular changes that confer immune suppression are not well understood. Mice exposed to TCDD during an acute B6-into-B6D2F1 graft-vs-host response do not develop disease, and recently this has been shown to correlate with the generation of CD4⁺ T cells that express CD25 and demonstrate in vitro suppressive function. The purpose of this study was to further characterize these CD4⁺ cells (TCDD-CD4⁺ cells) by comparing and contrasting them with both natural regulatory CD4⁺ T cells (T-regs) and vehicle-treated cells. Cellular anergy, suppressive functions, and cytokine production were examined. We found that TCDD-CD4⁺ cells actively proliferate in response to various stimuli but suppress IL-2 production and the proliferation of effector T cells. Like natural T-regs, TCDD-CD4⁺ cells do not produce IL-2 and their suppressive function is contact dependent but abrogated by costimulation through glucocorticoid-induced TNFR (GITR). TCDD-CD4⁺ cells also secrete significant amounts of IL-10 in response to both polyclonal and alloantigen stimuli. Several genes were significantly up-regulated in TCDD-CD4⁺ cells including TGF-β3, Blimp-1, and granzyme B, as well as genes associated with the IL12-Rb2 signaling pathway. TCDD-CD4⁺ cells demonstrated an increased responsiveness to IL-12 as indicated by the phosphorylation levels of STAT4. Only 2% of TCDD-CD4⁺ cells express Foxp3, suggesting that the AhR does not rely on Foxp3 for suppressive activity. The generation of CD4⁺ cells with regulatory function mediated through activation of the AhR by TCDD may represent a novel pathway for the induction of T-regs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants P01ES00040, P30ES00210, and T32ES07060.

² Address correspondence and reprint requests to Dr. Nancy I. Kerkvliet, Department of Environmental and Molecular Toxicology, 1007 Agriculture and Life Sciences Building, Oregon State University, Corvallis, OR 97331. E-mail address: nancy.kerkvliet{at}orst.edu

³ Abbreviations used in this paper: TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; AC, accessory cell; AhR, aryl hydrocarbon receptor; B6, C57BL/6 (mice); DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; F1, B6D2F1 (mice); GITR, glucocorticoid-induced TNFR; GVH, graft-vs-host; qPCR, semiquantitative PCR; TCCD-CD4⁺, TCDD-treated CD4⁺ T cell; T-reg, regulatory T cell; VEH-CD4⁺, vehicle-treated CD4⁺ T cell.

Related articles in The JI:

In This Issue

The JI 2008 181: 2261-2262. [Full Text]