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

Abstract

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 alpha(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.