Pulmonary CCR2+ CD4+ T cells are immune regulatory and attenuate lung fibrosis development

Thorax

Volumn 72, Issue 11, 2017, Pages 1007-1020

  Milger, Katrin ^a,b   Yu, Yingyan ^a,c   Brudy, Eva ^a   Irmler, Martin ^d   Skapenko, Alla ^b   Mayinger, Michael ^a   Lehmann, Mareike ^a   Beckers, Johannes ^d,e,f   Reichenberger, Frank ^g   Behr, Jürgen ^b,g   Eickelberg, Oliver ^a   Königshoff, Melanie ^a   Krauss Etschmann, Susanne ^a,c,g,h,i  

^a German Center for Lung Research (DZL)   (Germany)

^b UNIVERSITY OF MUNICH   (Germany)

^c LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^d INSTITUTE OF EPIDEMIOLOGY   (Germany)

^e TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^f GERMAN CENTER FOR DIABETES RESEARCH DZD   (Germany)

^g Asklepios Hospital Gauting   (Germany)

^h RESEARCH CENTER BORSTEL   (Germany)

ⁱ UNIVERSITY OF KIEL   (Germany)

Author keywords

CCR2+CD4+ T Cell; immunosuppressive; IPF; Pulmonary fibrosis

Indexed keywords

CHEMOKINE RECEPTOR; HERMES ANTIGEN; INTERLEUKIN 2 RECEPTOR ALPHA; L SELECTIN; MESSENGER RNA; TRANSCRIPTION FACTOR FOXP3; BIOLOGICAL MARKER; CCR2 PROTEIN, MOUSE; CHEMOKINE RECEPTOR CCR2;

ADOPTIVE TRANSFER; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRONCHOALVEOLAR LAVAGE FLUID; CCR2+ CD4+ T LYMPHOCYTE; CCR2- CD4+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD62L- CD44+ MEMORY T LYMPHOCYTE; COMPUTER MODEL; CONTROLLED STUDY; EXPERIMENTAL PULMONARY FIBROSIS; FEMALE; FIBROSING ALVEOLITIS; FLOW CYTOMETRY; FOXP3+ CD25 + T LYMPHOCYTE; HUMAN; HUMAN CELL; IMMUNOREGULATION; IN VITRO STUDY; MEMORY T LYMPHOCYTE; MOUSE; NONHUMAN; PRIORITY JOURNAL; RNA ANALYSIS; ANIMAL; C57BL MOUSE; COMPARATIVE STUDY; DISEASE MODEL; IMMUNOLOGY; INTERSTITIAL LUNG DISEASE; METABOLISM; PHENOTYPE; PREDICTIVE VALUE; REGULATORY T LYMPHOCYTE; SENSITIVITY AND SPECIFICITY; SEVERITY OF ILLNESS INDEX;

ANIMALS; BIOMARKERS; BRONCHOALVEOLAR LAVAGE FLUID; CD4-POSITIVE T-LYMPHOCYTES; DISEASE MODELS, ANIMAL; FEMALE; HUMANS; LUNG DISEASES, INTERSTITIAL; MICE; MICE, INBRED C57BL; PHENOTYPE; PREDICTIVE VALUE OF TESTS; RECEPTORS, CCR2; SENSITIVITY AND SPECIFICITY; SEVERITY OF ILLNESS INDEX; T-LYMPHOCYTES, REGULATORY;

EID: 85032031101     PISSN: 00406376     EISSN: 14683296     Source Type: Journal    
DOI: 10.1136/thoraxjnl-2016-208423     Document Type: Article

References (47)

1. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACIT Y): Two randomised trials. Lancet 2011;377:1760-9.
2. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071-82.
3. Homer RJ, Elias JA, Lee CG, et al. Modern concepts on the role of inflammation in pulmonary fibrosis. Arch Pathol Lab Med 2011;135:780-8.
4. Raghu G, Anstrom KJ, King TE, et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012;366:1968-77.
5. Carr MW, Roth SJ, Luther E, et al. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci USA 1994;91:3652-6.
6. Okuma T, Terasaki Y, Kaikita K, et al. C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinases. J Pathol 2004;204:594-604.
7. Moore BB, Paine R, Christensen PJ, et al. Protection from pulmonary fibrosis in the absence of CCR2 signaling. J Immunol 2001;167:4368-77.
8. Osterholzer JJ, Olszewski MA, Murdock BJ, et al. Implicating exudate macrophages and Ly-6C(high) monocytes in CCR2-dependent lung fibrosis following gene-targeted alveolar injury. J Immunol 2013;190:3447-57.
9. Baran CP, Opalek JM, McMaken S, et al. Important roles for macrophage colonystimulating factor, CC chemokine ligand 2, and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 2007;176:78-89.
10. Suga M, Iyonaga K, Ichiyasu H, et al. Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases. Eur Respir J 1999;14:376.
11. Mercer PF, Johns RH, Scotton CJ, et al. Pulmonary epithelium is a prominent source of proteinase-activated receptor-1-inducible CCL2 in pulmonary fibrosis. Am J Respir Crit Care Med 2009;179:414-25.
12. Raghu G, Martinez FJ, Brown KK, et al. CC-chemokine ligand 2 inhibition in idiopathic pulmonary fibrosis: A phase 2 trial of carlumab. Eur Respir J 2015;46:1740-50.
13. Hartl D, Griese M, Nicolai T, et al. A role for MCP-1/CCR2 in interstitial lung disease in children. Respir Res 2005;6:93.
14. Okuma T, Terasaki Y, Sakashita N, et al. MCP-1/CCR2 signalling pathway regulates hyperoxia-induced acute lung injury via nitric oxide production. Int J Exp Pathol 2006;87:475-83.
15. Königshoff M, Kramer M, Balsara N, et al. WNT1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J Clin Invest 2009;119:772-87.
16. Lo Re S, Lecocq M, Uwambayinema F, et al. Platelet-derived growth factor-producing CD4+ Foxp3+ regulatory T lymphocytes promote lung fibrosis. Am J Respir Crit Care Med 2011;184:1270-81.
17. Raghu G, Collard HR, Egan JJ, et al. An official AT S/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824.
18. Desbarats J, Wade T, Wade WF, et al. Dichotomy between naïve and memory CD4(+) T cell responses to Fas engagement. Proc Natl Acad Sci USA 1999;96:8104-9.
19. Luzina IG, Todd NW, Iacono AT, et al. Roles of T lymphocytes in pulmonary fibrosis. J Leukoc Biol 2008;83:237-44.
20. Trujillo G, Hartigan AJ, Hogaboam CM. T regulatory cells and attenuated bleomycininduced fibrosis in lungs of CCR7-/-mice. Fibrogenesis Tissue Repair 2010;3:18.
21. Fulkerson PC, Fischetti CA, Rothenberg ME. Eosinophils and CCR3 regulate interleukin-13 transgene-induced pulmonary remodeling. Am J Pathol 2006;169:2117-26.
22. Komai M, Tanaka H, Nagao K, et al. A novel CC-chemokine receptor 3 antagonist, Ki19003, inhibits airway eosinophilia and subepithelial/peribronchial fibrosis induced by repeated antigen challenge in mice. J Pharmacol Sci 2010;112:203-13.
23. Kleinewietfeld M, Puentes F, Borsellino G, et al. CCR6 expression defines regulatory effector/memory-like cells within the CD25(+)CD4+ T-cell subset. Blood 2005;105:2877-86.
24. Dürr C, Follo M, Idzko M, et al. Graft-versus-host disease reduces regulatory T-cell migration into the tumour tissue. Immunology 2012;137:80-8.
25. Zhang R, Borges CM, Fan MY, et al. Requirement for CD28 in effector regulatory T cell differentiation, CCR6 induction, and skin homing. J Immunol 2015; 195:4154-61.
26. Marchal-Sommé J, Uzunhan Y, Marchand-Adam S, et al. Cutting edge: Nonproliferating mature immune cells form a novel type of organized lymphoid structure in idiopathic pulmonary fibrosis. J Immunol 2006;176:5735-9.
27. Shalev I, Liu H, Koscik C, et al. Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis. J Immunol 2008;180:249-60.
28. Urbanellis P, Shyu W, Khattar R, et al. The regulatory T cell effector molecule fibrinogen-like protein 2 is necessary for the development of rapamycin-induced tolerance to fully MHC-mismatched murine cardiac allografts. Immunology 2015;144:91-106.
29. Cheng G, Yuan X, Tsai MS, et al. IL-2 receptor signaling is essential for the development of Klrg1+ terminally differentiated T regulatory cells. J Immunol 2012;189:1780-91.
30. Yuan X, Cheng G, Malek TR. The importance of regulatory T-cell heterogeneity in maintaining self-tolerance. Immunol Rev 2014;259:103-14.
31. Boveda-Ruiz D, DAlessandro-Gabazza CN, Toda M, et al. Differential role of regulatory T cells in early and late stages of pulmonary fibrosis. Immunobiology 2013;218.
32. L iu F, Liu J, Weng D, et al. CD4+CD25+Foxp3+ regulatory T cells depletion may attenuate the development of silica-induced lung fibrosis in mice. PLoS One 2010;5:e15404.
33. Lo Re S, Lison D, Huaux F. CD4+ T lymphocytes in lung fibrosis: Diverse subsets, diverse functions. J Leukoc Biol 2013;93:499-510.
34. G alati D, De Martino M, Trotta A, et al. Peripheral depletion of NK cells and imbalance of the Treg/Th17 axis in idiopathic pulmonary fibrosis patients. Cytokine 2014;66:119-26.
35. a RR, Peng H, a ML, et al. Semaphorin 7a+ regulatory T cells are associated with progressive IPF and are implicated in TGF-1-induced pulmonary fibrosis. Am J Respir Crit Care Med 2012;41:1.
36. Peng X, Moore MW, Peng H, et al. CD4+CD25+FoxP3+ regulatory Tregs inhibit fibrocyte recruitment and fibrosis via suppression of FGF-9 production in the TGF-1 exposed murine lung. Front Pharmacol 2014;5:80.
37. Kotsianidis I, Nakou E, Bouchliou I, et al. Global impairment of CD4+CD25+FOXP3+ regulatory T cells in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179:1121-30.
38. Garibaldi BT, D'Alessio FR, Mock JR, et al. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. Am J Respir Cell Mol Biol 2013;48:35-43.
39. Martinez JA, King TE, Brown K, et al. Increased expression of the interleukin-10 gene by alveolar macrophages in interstitial lung disease. Am J Physiol 1997;273:L676-83.
40. Bergeron A, Soler P, Kambouchner M, et al. Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10. Eur Respir J 2003;22:69-76.
41. Sun L, Louie MC, Vannella KM, et al. New concepts of IL-10-induced lung fibrosis: Fibrocyte recruitment and M2 activation in a CCL2/CCR2 axis. Am J Physiol Lung Cell Mol Physiol 2011;300:L341-53.
42. Huaux F, Louahed J, Hudspith B, et al. Role of interleukin-10 in the lung response to silica in mice. Am J Respir Cell Mol Biol 1998;18:51-9.
43. Hasegawa H, Inoue A, Muraoka M, et al. Therapy for pneumonitis and sialadenitis by accumulation of CCR2-expressing CD4+CD25+ regulatory T cells in MRL/lpr mice. Arthritis Res Ther 2007;9:R15.
44. Herazo-Maya JD, Noth I, Duncan SR, et al. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med 2013;5:205ra136.
45. Sekiya T, Kashiwagi I, Yoshida R, et al. Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis. Nat Immunol 2013;14:230-7.
46. Palumbo-Zerr K, Zerr P, Distler A, et al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-signaling and fibrosis. Nat Med 2015;21:150-8.
47. Brühl H, Cihak J, Schneider MA, et al. Dual role of CCR2 during initiation and progression of collagen-induced arthritis: Evidence for regulatory activity of CCR2+ T cells. J Immunol 2004;172:890-8.