title: Regulatory T cells negatively regulate neovasculature of airway remodeling via DLL4-Notch signaling.
abstract: Regulatory T cells (Treg) have been shown to prevent the development of allergic asthma; however, the role of Treg in asthma with established airway remodeling is unknown. To address this, we exploited an OVA-induced chronic asthma mouse model wherein Treg were adoptively transferred to the mice at chronic stage of the model. We found that among the structural alterations of airway remodeling, Treg selectively reduced the vessel numbers in both peritracheal and peribronchial regions and the lung parenchyma. Extracellular matrix deposition, mucus metaplasia, muscular hyperplasia, and vasodilation, as were also induced by chronic allergen challenge, were not affected by Treg. TUNEL staining of the lung sections revealed an increased endothelial cell (EC) apoptosis in mice receiving Treg transfers compared with their asthmatic counterparts. By using Matrigel angiogenesis assays, we showed that Treg inhibited EC angiogenesis both in vitro and in vivo. Treg preferentially expressed Notch ligand DLL4, and an anti-DLL4 blocking Ab abrogated the inhibitory effect of Treg on EC tube formation. In vivo, decreased airway and lung vessel numbers as well as ameliorated airway hyperresponsiveness after Treg transfers were reverted when Treg-derived DLL4 signal was blocked by the anti-DLL4 Ab. Our findings demonstrate a novel function of Treg whereby Treg down-regulate remodeling angiogenesis via proapoptotic DLL4-Notch signaling, and suggest a therapeutic potential of Treg in alleviating airway hyperresponsiveness of chronic asthma.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Miao-Tzu
authors.initials: MT
authors.lastname: Huang
authors.forename: Yang-Shia
authors.initials: YS
authors.lastname: Dai
authors.forename: Yu-Bin
authors.initials: YB
authors.lastname: Chou
authors.forename: Yi-Hsiu
authors.initials: YH
authors.lastname: Juan
authors.forename: Chih-Chiang
authors.initials: CC
authors.lastname: Wang
authors.forename: Bor-Luen
authors.initials: BL
authors.lastname: Chiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D002908:Chronic Disease; D015536:Down-Regulation / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000276:immunology*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch