Foxp3+ regulatory T cells promote lung epithelial proliferation

Mucosal Immunol. 2014 Nov;7(6):1440-51. doi: 10.1038/mi.2014.33. Epub 2014 May 21.

Abstract

Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality each year. There is a paucity of information regarding the mechanisms necessary for ARDS resolution. Foxp3(+) regulatory T cells (Foxp3(+) T(reg) cells) have been shown to be an important determinant of resolution in an experimental model of lung injury. We demonstrate that intratracheal delivery of endotoxin (lipopolysaccharide) elicits alveolar epithelial damage from which the epithelium undergoes proliferation and repair. Epithelial proliferation coincided with an increase in Foxp3(+) T(reg) cells in the lung during the course of resolution. To dissect the role that Foxp3(+) T(reg) cells exert on epithelial proliferation, we depleted Foxp3(+) T(reg) cells, which led to decreased alveolar epithelial proliferation and delayed lung injury recovery. Furthermore, antibody-mediated blockade of CD103, an integrin, which binds to epithelial expressed E-cadherin decreased Foxp3(+) T(reg) numbers and decreased rates of epithelial proliferation after injury. In a non-inflammatory model of regenerative alveologenesis, left lung pneumonectomy, we found that Foxp3(+) T(reg) cells enhanced epithelial proliferation. Moreover, Foxp3(+) T(reg) cells co-cultured with primary type II alveolar cells (AT2) directly increased AT2 cell proliferation in a CD103-dependent manner. These studies provide evidence of a new and integral role for Foxp3(+) T(reg) cells in repair of the lung epithelium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / immunology*
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Cell Proliferation*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Integrin alpha Chains / genetics
  • Integrin alpha Chains / immunology
  • Lipopolysaccharides / toxicity
  • Mice
  • Mice, Knockout
  • Respiratory Distress Syndrome / chemically induced
  • Respiratory Distress Syndrome / genetics
  • Respiratory Distress Syndrome / immunology*
  • Respiratory Distress Syndrome / pathology
  • Respiratory Mucosa / immunology*
  • Respiratory Mucosa / pathology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology

Substances

  • Antigens, CD
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Integrin alpha Chains
  • Lipopolysaccharides
  • alpha E integrins