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Forkhead Box P3 Regulates TLR10 Expression in Human T Regulatory Cells¹

Mayo Clinic, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Rochester, MN 55905

Although functionally relevant TLRs can be expressed on human T regulatory (Treg) cells, little is known about the transcriptional control of their expression. We hypothesized that the transcription factor forkhead box P3 (FOXP3) regulates the expression of TLR family members in human Treg cells. Using primary human T cells and a reporter assay in Jurkat T cell lines, we dissected the regulation of TLR10, a TLR highly expressed in human Treg cells. We determined that TLR10 was expressed in human Treg cells through quantitative PCR, Western blotting, and flow cytometry. DNA binding of FOXP3 to a suspected cis-regulatory region in proximity to the transcription start site of TLR10 was established through EMSA and chromatin immunoprecipitation. Transcriptional control of TLR10 by FOXP3 was determined through luciferase reporter assays in Jurkat T cell lines. Relevance of FOXP3 to TLR10 gene transcription in primary T cells was established through the transfection of primary CD4⁺CD25^–FOXP3^– T cells with a FOXP3 expression vector, which resulted in prompt production of TLR10 mRNA. Enhanced expression of TLR10 protein in primary Treg cells was induced in a calcium-dependent fashion through TCR activation. The suspected promotional cooperation between FOXP3 and NF-AT was established in the abolition of the luciferase signal upon transfection of a mutant FOXP3 devoid of NF-AT-binding activity. These results suggest that human Treg cells express TLR10, and this expression is regulated through a cooperative complex of FOXP3 and NF-AT.

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 made possible through the Dana Foundation Human Immunology Award and National Institutes of Health Grant DK64194-04.

² Address correspondence and reprint requests to Dr. William A. Faubion, Jr., Mayo Clinic, Department of Internal Medicine, Division of Gastroenterology and Hepatology, 200 1st Street SW, Rochester, MN 55905. E-mail address: Faubion.William{at}mayo.edu

³ Abbreviations used in this paper: Treg, T regulatory; ChIP, chromatin immunoprecipitation; FKH, forkhead; FOXP3, forkhead box P3; shRNA, short hairpinned RNA; siRNA, small interfering RNA; TSS, transcription start site.