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Regulation of T Cell Activation by Notch Ligand, DLL4, Promotes IL-17 Production and Rorc Activation

University of Michigan Medical School, Department of Pathology, Ann Arbor, MI 48109

The activation and differentiation of T cells are dependent upon numerous initiating events that are influenced by the immune environment, nature of the Ag, as well as the activation state of APCs. In the present studies we have investigated the role of a specific notch ligand, delta-like 4 (Dll4). In particular, our data have indicated that Dll4 is inducible by pathogen-associated signals through TLR activation on dendritic cells but not early response inflammatory cytokines, IL-1 and IL-18 that also activate cells via MyD88 adapter pathway. Our observations from in vitro cultures confirmed earlier reports demonstrating that Dll4 inhibits Th2 cytokine production. Furthermore, Dll4 influences the generation of IL-17-producing T cells in the presence of additional skewing cytokines, IL-6 and TGF-β. In the absence of notch signals, IL-17 production was significantly inhibited even under specific skewing conditions. These studies further demonstrate that Dll4 up-regulates Rorc expression in T cells and that both Rorc and Il17 gene promoters are direct transcriptional notch targets that further enhance the differentiation of Th17 cell populations. Thus, facilitation of efficient T cell differentiation may depend upon the activation of T cells via specific notch ligand stimulation.

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 Nicholas W. Lukacs, University of Michigan Medical School, 4059 BSRB, 109 Zina Pitcher, Ann Arbor, MI 48109-2200. E-mail address: nlukacs{at}umich.edu

² Abbreviations used in this paper: PAMP, pathogen associated molecular pattern; DC, dendritic cell; Dll, delta-like; N-ICD, notch intracellular domain; MAML, Mastermind protein; GSI, -secretase inhibitor; ChIP, chromatin immunoprecipitation; rD114, recombinant Dll4; BM, bone marrow; WT, wild type; TSS, translational start site.

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The JI 2009 182: 7329-7330. [Full Text]