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Notch1 Signaling and Regulatory T Cell Function

Naoki Asano^*, Tomohiro Watanabe^*,, Atsushi Kitani^*, Ivan J. Fuss^* and Warren Strober^1,*

^* Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

Previous studies have shown that the Notch1 and TGF-β signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-β signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-Jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-β signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-β signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-β-mediated effector function of Tregs.

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 Address correspondence and reprint requests to Dr. Warren Strober, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-Clinical Research Center, Mail Stop Code 1890, 10 Center Drive, Bethesda, MD 20892. E-mail address: wstrober{at}niaid.nih.gov

² Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; NICD, Notch1 intracellular domain; MLEC-PAI-1, luciferase reporter construct mink lung epithelial cells stably expressing plasminogen activation inhibtor-1 luciferase reporter construct; GSI, -secretase inhibitor.