CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury

被引:438
作者
D'Alessio, Franco R.
Tsushima, Kenji
Aggarwal, Neil R.
West, Erin E.
Willett, Matthew H.
Britos, Martin F.
Pipeling, Matthew R.
Brower, Roy G.
Tuder, Rubin M. [2 ]
McDyer, John F.
King, Landon S. [1 ]
机构
[1] Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, Div Pulm & Crit Care Med,Dept Med, Baltimore, MD 21224 USA
[2] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA
关键词
REGULATORY T-CELLS; GROWTH-FACTOR-BETA; EUROPEAN CONSENSUS CONFERENCE; TGF-BETA; DENDRITIC CELLS; ALTERNATIVE ACTIVATION; IMMUNE-RESPONSES; INFLAMMATION; RESOLUTION; LYMPHOCYTES;
D O I
10.1172/JCI36498
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 clay 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-beta and neutrophil apoptosis. Mechanistically, Treg-mediated resolution of lung injury was abrogated by TGF-beta inhibition. Moreover, BAL of patients with ALI revealed dynamic changes in CD3(+)CD4(+)CD25(hi)CD127(lo)Foxp3(+) 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.
引用
收藏
页码:2898 / 2913
页数:16
相关论文
共 83 条
[31]   Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke [J].
Liesz, Arthur ;
Suri-Payer, Elisabeth ;
Veltkamp, Claudia ;
Doerr, Henrike ;
Sommer, Clemens ;
Rivest, Serge ;
Giese, Thomas ;
Veltkamp, Roland .
NATURE MEDICINE, 2009, 15 (02) :192-199
[32]   TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells [J].
Marie, JC ;
Letterio, JJ ;
Gavin, M ;
Rudensky, AY .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 201 (07) :1061-1067
[33]   Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-β receptor [J].
Marie, Julien C. ;
Liggitt, Denny ;
Rudensky, Alexander Y. .
IMMUNITY, 2006, 25 (03) :441-454
[34]   Science review: Apoptosis in acute lung injury [J].
Matute-Bello, G ;
Martin, TR .
CRITICAL CARE, 2003, 7 (05) :355-358
[35]  
McCormick LL, 1999, J IMMUNOL, V163, P5693
[36]   Natural recovery and protection from autoimmune encephalomyelitis:: Contribution of CD4+CD25+ regulatory cells within the central nervous system [J].
McGeachy, MJ ;
Stephens, LA ;
Anderton, SM .
JOURNAL OF IMMUNOLOGY, 2005, 175 (05) :3025-3032
[37]   Regulatory T cells dampen pulmonary inflammation and lung injury in an animal model of Pneumocystis pneumonia [J].
McKinley, Laura ;
Logar, Alison J. ;
McAllister, Florencia ;
Zheng, Mingquan ;
Steele, Chad ;
Kolls, Jay K. .
JOURNAL OF IMMUNOLOGY, 2006, 177 (09) :6215-6226
[38]   Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1 [J].
Mei, Shirley H. J. ;
McCarter, Sarah D. ;
Deng, Yupu ;
Parker, Colleen H. ;
Liles, W. Conrad ;
Stewart, Duncan J. .
PLOS MEDICINE, 2007, 4 (09) :1525-1537
[39]   Association of Foxp3 regulatory gene expression with graft-versus-host disease [J].
Miura, Y ;
Thoburn, CJ ;
Bright, EC ;
Phelps, ML ;
Shin, T ;
Matsui, EC ;
Matsui, WH ;
Arai, S ;
Fuchs, EJ ;
Vogelsang, GB ;
Jones, RJ ;
Hess, AD .
BLOOD, 2004, 104 (07) :2187-2193
[40]   Protective role of macrophages in noninflammatory lung injury caused by selective ablation of alveolar epithelial type II cells [J].
Miyake, Yasunobu ;
Kaise, Hitomi ;
Isono, Kyo-ichi ;
Koseki, Haruhiko ;
Kohno, Kenji ;
Tanaka, Masato .
JOURNAL OF IMMUNOLOGY, 2007, 178 (08) :5001-5009