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
[1]   The American-European Consensus Conference on ARDS, Part 2 - Ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling [J].
Artigas, A ;
Bernard, GR ;
Carlet, J ;
Dreyfuss, D ;
Gattinoni, L ;
Hudson, L ;
Lamy, M ;
Marini, JJ ;
Matthay, MA ;
Pinsky, MR ;
Spragg, R ;
Suter, PM ;
Blanch, L ;
Burchardi, H ;
Hedenstierna, C ;
Lemaire, F ;
Roussos, C ;
Mancebo, J ;
Morris, A ;
Pesenti, A ;
Rossi, A ;
Van Asbeck, BS ;
Brigham, KL ;
Dhainaut, JF ;
Fowler, AA ;
Hyers, TM ;
Morel, D ;
Rodriguez-Roisin, R ;
Schaller, MD ;
Hemmer, M ;
Torres, A ;
Villar, J ;
Vincent, JL ;
Leeper, K ;
Meyrick, B ;
Oppenheimer, L ;
Reid, L ;
Murray, JF ;
Bihari, D ;
Bosken, C ;
Goris, J ;
Johanson, WJ ;
Lanken, PN ;
Le Gall, JR ;
Morris, AH ;
Rinaldo, J ;
Pattishal, EN .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1998, 157 (04) :1332-1347
[2]   Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis [J].
Balandina, A ;
Lécart, S ;
Dartevelle, P ;
Saoudi, A ;
Berrih-Aknin, S .
BLOOD, 2005, 105 (02) :735-741
[3]   Natural regulatory T cells in infectious disease [J].
Belkaid, Y ;
Rouse, BT .
NATURE IMMUNOLOGY, 2005, 6 (04) :353-360
[4]   The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 [J].
Bennett, CL ;
Christie, J ;
Ramsdell, F ;
Brunkow, ME ;
Ferguson, PJ ;
Whitesell, L ;
Kelly, TE ;
Saulsbury, FT ;
Chance, PF ;
Ochs, HD .
NATURE GENETICS, 2001, 27 (01) :20-21
[5]   THE AMERICAN-EUROPEAN CONSENSUS CONFERENCE ON ARDS - DEFINITIONS, MECHANISMS, RELEVANT OUTCOMES, AND CLINICAL-TRIAL COORDINATION [J].
BERNARD, GR ;
ARTIGAS, A ;
BRIGHAM, KL ;
CARLET, J ;
FALKE, K ;
HUDSON, L ;
LAMY, M ;
LEGALL, JR ;
MORRIS, A ;
SPRAGG, R ;
COCHIN, B ;
LANKEN, PN ;
LEEPER, KV ;
MARINI, J ;
MURRAY, JF ;
OPPENHEIMER, L ;
PESENTI, A ;
REID, L ;
RINALDO, J ;
VILLAR, J ;
VANASBECK, BS ;
DHAINAUT, JF ;
MANCEBO, J ;
MATTHAY, M ;
MEYRICK, B ;
PAYEN, D ;
PERRET, C ;
FOWLER, AA ;
SCHALLER, MD ;
HUDSON, LD ;
HYERS, T ;
KNAUS, W ;
MATTHAY, R ;
PINSKY, M ;
BONE, RC ;
BOSKEN, C ;
JOHANSON, WG ;
LEWANDOWSKI, K ;
REPINE, J ;
RODRIGUEZROISIN, R ;
ROUSSOS, C ;
ANTONELLI, MA ;
BELOUCIF, S ;
BIHARI, D ;
BURCHARDI, H ;
LEMAIRE, F ;
MONTRAVERS, P ;
PETTY, TL ;
ROBOTHAM, J ;
ZAPOL, W .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 1994, 149 (03) :818-824
[6]   FOXP3 modifies the phenotypic and functional properties of regulatory T cells [J].
Campbell, Daniel J. ;
Ziegler, Steven F. .
NATURE REVIEWS IMMUNOLOGY, 2007, 7 (04) :305-310
[7]   Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide [J].
Caramalho, I ;
Lopes-Carvalho, T ;
Ostler, D ;
Zelenay, S ;
Haury, M ;
Demengeot, J .
JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 197 (04) :403-411
[8]   Natural killer T cells and CD8+ T cells are dispensable for T cell-dependent allergic airway inflammation [J].
Das, Jyoti ;
Eynott, Paul ;
Jupp, Ray ;
Bothwell, Alfred ;
Van Kaer, Luc ;
Shi, Yufang ;
Das, Gobardhan .
NATURE MEDICINE, 2006, 12 (12) :1345-1346
[9]   The interrelated roles of TGF-β and IL-10 in the regulation of experimental colitis [J].
Fuss, IJ ;
Boirivant, M ;
Lacy, B ;
Strober, W .
JOURNAL OF IMMUNOLOGY, 2002, 168 (02) :900-908
[10]   EFFECT OF ANTIBODY TO TRANSFORMING GROWTH-FACTOR-BETA ON BLEOMYCIN-INDUCED ACCUMULATION OF LUNG COLLAGEN IN MICE [J].
GIRI, SN ;
HYDE, DM ;
HOLLINGER, MA .
THORAX, 1993, 48 (10) :959-966