CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury
Open Access
- 1 October 2009
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 119 (10), 2898-2913
- https://doi.org/10.1172/jci36498
Abstract
Acute lung injury (ALI) is characterized by rapid alveolar injury, inflammation, cytokine induction, and neutrophil accumulation. Although early events in the pathogenesis of ALI have been defined, the mechanisms underlying resolution are unknown. As a model of ALI, we administered intratracheal (i.t.) LPS to mice and observed peak lung injury 4 days after the challenge, with resolution by day 10. Numbers of alveolar lymphocytes increased as injury resolved. To examine the role of lymphocytes in this response, lymphocyte-deficient Rag-1–/– and C57BL/6 WT mice were exposed to i.t. LPS. The extent of injury was similar between the groups of mice through day 4, but recovery was markedly impaired in the Rag-1–/– mice. Adoptive transfer studies revealed that infusion of CD4+CD25+Foxp3+ Tregs as late as 24 hours after i.t. LPS normalized resolution in Rag-1–/– mice. Similarly, Treg depletion in WT mice delayed recovery. Treg transfer into i.t. LPS–exposed Rag-1–/– mice also corrected the elevated levels of alveolar proinflammatory cytokines and increased the diminished levels of alveolar TGF-β and neutrophil apoptosis. Mechanistically, Treg-mediated resolution of lung injury was abrogated by TGF-β inhibition. Moreover, BAL of patients with ALI revealed dynamic changes in CD3+CD4+CD25hiCD127loFoxp3+ cells. These results indicate that Tregs modify innate immune responses during resolution of lung injury and suggest potential targets for treating ALI, for which there are no specific therapies currently available.Keywords
This publication has 87 references indexed in Scilit:
- TGF-β and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3Proceedings of the National Academy of Sciences of the United States of America, 2008
- How regulatory T cells workNature Reviews Immunology, 2008
- CD4+CD25+Foxp3+regulatory T cells induce alternative activation of human monocytes/macrophagesProceedings of the National Academy of Sciences of the United States of America, 2007
- Adaptive immune cells temper initial innate responsesNature Medicine, 2007
- Resolution of inflammation: the beginning programs the endNature Immunology, 2005
- Natural regulatory T cells in infectious diseaseNature Immunology, 2005
- Potential role of interleukin-10-secreting regulatory T cells in allergy and asthmaNature Reviews Immunology, 2005
- T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpuraNature Medicine, 2003
- Alternative activation of macrophagesNature Reviews Immunology, 2003
- Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory diseaseNature, 1992