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Polarized Localization of Epithelial CXCL11 in Chronic Obstructive Pulmonary Disease and Mechanisms of T Cell Egression¹

Joanna C. Porter^2,4,*,, Mary Falzon^2, and Alan Hall^2,3,*

^* Medical Research Council Laboratory of Molecular Cell Biology, University College London, London; Department of Respiratory Medicine, University College London Hospitals National Health Service Trust, University College London Hospital, London; and Department of Histopathology, Rockefeller Building, London

The exit of lymphocytes from the interstitium of the lung, across the bronchial epithelium and into the airway lumen, is known as egression, or luminal clearance. Egression is important for immune surveillance and the resolution of inflammation, but the mechanisms involved are unknown. We show that egression of human T cells across the bronchial epithelium is a multistep process, driven in part by a polarized transepithelial gradient of CXCL11 that is up-regulated in patients with chronic obstructive airways disease. Previous studies have shown that T cells can migrate across a disrupted bronchial epithelium, but we provide evidence that egression does not require epithelial injury, and can take place across an intact epithelial barrier. After negotiating the extracellular matrix, the T cell adheres to the basal surface of the bronchial epithelial cell using ₄ and leukocyte function associated-1 integrins before crossing the epithelium in an leukocyte function associated-1-dependent way. We demonstrate an egression-dependent decrease in transepithelial resistance across the epithelium without gross alteration in tight-junction proteins. The process of egression has been relatively overlooked when considering the control of leukocyte trafficking in the lung and other epithelial organs. This study highlights the role of the respiratory epithelium in the trafficking of T lymphocytes from the pulmonary interstitium and into the large airways, during the onset and resolution of pulmonary inflammation.

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 Cancer Research (CR) U.K. and a Wellcome Trust Advanced Clinical Fellowship (to J.C.P.).

² J.P. and A.H. designed the project and wrote the paper. J.P. performed the experiments. M.F. and J.P. selected samples for histopathology and interpreted the histopathological findings.

³ Current address: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 572, New York, NY 10065.

⁴ Address correspondence and reprint requests to Dr. Joanna C. Porter, Medical Research Council Laboratory of Molecular Cell Biology, University College London, London WC1E 6BT, U.K. E-mail address: Joanna.porter{at}ucl.ac.uk

⁵ Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; TER, transepithelial electrical resistance; ZO-1, zona-occludens; LFA-1, leukocyte function associated-1; NHBE, normal human bronchial epithelial cell.

⁶ The online version of this article contains supplemental material.