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Suppression of Th2 Cell Development by Notch Ligands Delta1 and Delta4¹

Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104

Notch signaling plays important roles in Th cell activation. We show that in response to TLR ligation, dendritic cells up-regulate expression of Notch ligands Delta1 and Delta4 via a MyD88-dependent pathway. Expression of Delta1 or Delta4 by dendritic cells enhanced their ability to activate naive Th cells and promote Th1 cell development, and allowed them to strongly inhibit Th2 cell development. Promotion of Th1 cell development was dependent on IFN- and T-bet expression by responding Th cells. However, the inhibition of Th2 cell development occurred independently of IFN- or T-bet, and resulted from a block in IL-4-initiated commitment to the Th2 lineage. The promotion of Th1 cell development by Delta is not a reflection of the delivery of pro-Th1 instructional signal, but rather it is the result of a block in the downstream effects initiated by IL-4 signaling.

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 Grant AI53825 (to E.J.P.). E.J.P. is a Burroughs Wellcome Fund Scholar in Molecular Parasitology. C.M.K. is supported by the Canadian Institutes of Health Research and the International Human Frontier Science Program Organization.

² Address correspondence and reprint requests to Dr. Edward J. Pearce, Department of Pathobiology, Room 318 Hill Pavilion, School of Veterinary Medicine, 380 South University Avenue, Philadelphia, PA 19104. E-mail address: ejpearce{at}mail.med.upenn.edu

³ Abbreviations used in this paper: DC, dendritic cell; LLO, listeriolysin O; NICD, intracellular domain of Notch.

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