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,¶
Departments of
* Medical Research,
Dermatology,
Internal Medicine, and
Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; and
¶ Graduate Institute of Clinical Medicine, School of Medicine, National Taiwan University, Taipei, Taiwan
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.
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 grants from the National Taiwan University Hospital (NTUH-94A21, NTUH-95A08, NTUH-96A07, and NTUH-97A02) and the National Science Council, Taiwan (NSC94-2312-B-002-009, NSC95-2320-B-002-059, and NSC96-2314-B-002-037-MY3).
2 Address correspondence and reprint requests to Dr. Bor-Luen Chiang, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, School of Medicine, National Taiwan University, No. 7, Chung-Shan S RD, Taipei, Taiwan 100. E-mail address: gicmbor{at}ntu.edu.tw
3 Abbreviations used in this paper: Treg, regulatory T cell; 
-SMA, -smooth muscle actin; AHR, airway hyperresponsiveness; ASM, airway smooth muscle; BALF, bronchoalveolar lavage fluid; EC, endothelial cell; ECM, extracellular matrix; MPEC, murine pulmonary EC; ProCol, procollagen; Teff, effector T cell; VEGF, vascular endothelial growth factor.
4 The online version of this article contains supplemental material.
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