Subscribe to RSS
DOI: 10.1055/a-2703-4491
T Regulatory Mechanisms in Airway and Interstitial Lung Disease
Authors
Funding This study was supported by the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases (grant nos.: T32AI007046 and U19AI162310).

Abstract
Chronic lung disease is a sequela of unresolving pathogenesis in the lung. Current estimates report approximately 7.4% of the world's population live with chronic respiratory diseases. The architectural differences in the airways and individual alveoli provide unique microenvironments for mechanisms of disease and thus necessitate specialized modes of regulation. A key immune cell type that has the ability to adapt and provide copius regulatory mechanisms are T regulatory cells (Tregs). In the last two decades, studies have revealed that Tregs respond to their microenvironment and phenotypically change to conduct versatile functions; however, during chronic inflammatory diseases, Tregs are potentially skewed toward pathogenic mechanisms. In this review, we will focus on the differential mechanisms of Treg responses in the lung airways versus interstitium as unique microenvironments by focusing on asthma, acute lung injury/airway respiratory disease syndrome, and interstitial lung disease.
Keywords
T regulatory cells - Tregs - asthma - acute lung injury - acute respiratory distress syndrome - interstitial lung diseasePublication History
Received: 23 April 2025
Accepted: 16 September 2025
Accepted Manuscript online:
18 September 2025
Article published online:
10 October 2025
© 2025. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 Itoh M, Takahashi T, Sakaguchi N. et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 1999; 162 (09) 5317-5326
- 2 Suri-Payer E, Amar AZ, Thornton AM, Shevach EM. CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J Immunol 1998; 160 (03) 1212-1218
- 3 Khattri R, Cox T, Yasayko S-A, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003; 4 (04) 337-342
- 4 Bacchetta R, Roncarolo MG. IPEX syndrome from diagnosis to cure, learning along the way. J Allergy Clin Immunol 2024; 153 (03) 595-605
- 5 Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007; 8 (02) 191-197
- 6 Dikiy S, Rudensky AY. Principles of regulatory T cell function. Immunity 2023; 56 (02) 240-255
- 7 Collison LW, Workman CJ, Kuo TT. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007; 450 (7169): 566-569
- 8 Wei X, Zhang J, Gu Q. et al. Reciprocal expression of IL-35 and IL-10 defines two distinct effector Treg subsets that are required for maintenance of immune tolerance. Cell Rep 2017; 21 (07) 1853-1869
- 9 Ohkura N, Sakaguchi S. Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases. Cell Res 2020; 30 (06) 465-474
- 10 Carroll N, Elliot J, Morton A, James A. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993; 147 (02) 405-410
- 11 Pividori M, Schoettler N, Nicolae DL, Ober C, Im HK. Shared and distinct genetic risk factors for childhood-onset and adult-onset asthma: genome-wide and transcriptome-wide studies. Lancet Respir Med 2019; 7 (06) 509-522
- 12 Camoretti-Mercado B, Lockey RF. Airway smooth muscle pathophysiology in asthma. J Allergy Clin Immunol 2021; 147 (06) 1983-1995
- 13 Tohda Y, Kubo H, Ito M, Fukuoka M, Nakajima S. Histopathology of the airway epithelium in an experimental dual-phase model of bronchial asthma. Clin Exp Allergy 2001; 31 (01) 135-143
- 14 Soriano JB. et al; GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med 2017; 5 (09) 691-706
- 15 Brusselle G, Kips J, Joos G, Bluethmann H, Pauwels R. Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. Am J Respir Cell Mol Biol 1995; 12 (03) 254-259
- 16 Grünig G, Warnock M, Wakil AE. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998; 282 (5397): 2261-2263
- 17 Hogan SP, Koskinen A, Foster PS. Interleukin-5 and eosinophils induce airway damage and bronchial hyperreactivity during allergic airway inflammation in BALB/c mice. Immunol Cell Biol 1997; 75 (03) 284-288
- 18 Wills-Karp M, Luyimbazi J, Xu X. et al. Interleukin-13: central mediator of allergic asthma. Science 1998; 282 (5397): 2258-2261
- 19 Rubtsov YP, Rasmussen JP, Chi EY. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008; 28 (04) 546-558
- 20 Coomes SM, Kannan Y, Pelly VS. et al. CD4+ Th2 cells are directly regulated by IL-10 during allergic airway inflammation. Mucosal Immunol 2017; 10 (01) 150-161
- 21 Golebski K, Layhadi JA, Sahiner U. et al. Induction of IL-10-producing type 2 innate lymphoid cells by allergen immunotherapy is associated with clinical response. Immunity 2021; 54 (02) 291-307.e7
- 22 Braza F, Chesne J, Durand M. et al. A regulatory CD9(+) B-cell subset inhibits HDM-induced allergic airway inflammation. Allergy 2015; 70 (11) 1421-1431
- 23 Qian G, Jiang W, Sun D. et al. B-cell-derived IL-10 promotes allergic sensitization in asthma regulated by Bcl-3. Cell Mol Immunol 2023; 20 (11) 1313-1327
- 24 Mäkelä MJ, Kanehiro A, Borish L. et al. IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization. Proc Natl Acad Sci U S A 2000; 97 (11) 6007-6012
- 25 Wilson MS, Elnekave E, Mentink-Kane MM. et al. IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice. J Clin Invest 2007; 117 (10) 2941-2951
- 26 Kearley J, Barker JE, Robinson DS, Lloyd CM. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med 2005; 202 (11) 1539-1547
- 27 Saheb Sharif-Askari F, Zakri AM, Alenazy MF. et al. IL-35 promotes IL-35+IL-10+ Bregs and conventional LAG3+ Tregs in the lung tissue of OVA-induced asthmatic mice. Inflamm Res 2024; 73 (10) 1699-1709
- 28 Chen T, Hou X, Ni Y. et al. The imbalance of FOXP3/GATA3 in regulatory T cells from the peripheral blood of asthmatic patients. J Immunol Res 2018; 2018: 3096183
- 29 Shi Y-H, Shi GC, Wan HY. et al. An increased ratio of Th2/Treg cells in patients with moderate to severe asthma. Chin Med J (Engl) 2013; 126 (12) 2248-2253
- 30 Ying S, O'Connor B, Ratoff J. et al. Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol 2008; 181 (04) 2790-2798
- 31 Skrgat S, Malovrh MM, Sarc I. et al. TSLP as biomarker in asthma patients. Eur Respir J 2015; 46 (Suppl. 59) PA3868
- 32 Nguyen KD, Vanichsarn C, Nadeau KC. TSLP directly impairs pulmonary Treg function: association with aberrant tolerogenic immunity in asthmatic airway. Allergy Asthma Clin Immunol 2010; 6 (01) 4
- 33 Gurram RK, Li P, Oh J. et al. TSLP acts on regulatory T cells to maintain their identity and limit allergic inflammation. Sci Immunol 2025; 10 (103) eadk0073
- 34 Khumalo J, Kirstein F, Hadebe S, Brombacher F. IL-4Rα signaling in CD4+CD25+FoxP3+ T regulatory cells restrains airway inflammation via limiting local tissue IL-33. JCI Insight 2020; 5 (20) e136206
- 35 Zhou JY, Alvarez CA, Cobb BA. Integration of IL-2 and IL-4 signals coordinates divergent regulatory T cell responses and drives therapeutic efficacy. eLife 2021; 10: e57417
- 36 Zhu X, Chen Q, Liu Z, Luo D, Li L, Zhong Y. Low expression and hypermethylation of FOXP3 in regulatory T cells are associated with asthma in children. Exp Ther Med 2020; 19 (03) 2045-2052
- 37 Smyth LJC, Eustace A, Kolsum U, Blaikely J, Singh D. Increased airway T regulatory cells in asthmatic subjects. Chest 2010; 138 (04) 905-912
- 38 Hoseini-Shahrestanak S, Bazargan N, Rahimian L, Nemati M, Solaymani S, Jafarzadeh A. Imbalanced expression of Th2 and Treg cell-related parameters in peripheral blood mononuclear cells in patients with allergic asthma. Tanaffos 2018; 17 (01) 1-12
- 39 Mantel P-Y, Kuipers H, Boyman O. et al. GATA3-driven Th2 responses inhibit TGF-β1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol 2007; 5 (12) e329
- 40 Gri G, Piconese S, Frossi B. et al. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 2008; 29 (05) 771-781
- 41 Farne H, Jackson DJ, Johnston SL. Are emerging PGD2 antagonists a promising therapy class for treating asthma?. Expert Opin Emerg Drugs 2016; 21 (04) 359-364
- 42 Sawyer N, Cauchon E, Chateauneuf A. et al. Molecular pharmacology of the human prostaglandin D2 receptor, CRTH2. Br J Pharmacol 2002; 137 (08) 1163-1172
- 43 Matsuoka T, Hirata M, Tanaka H. et al. Prostaglandin D2 as a mediator of allergic asthma. Science 2000; 287 (5460): 2013-2017
- 44 Chantveerawong T, Sangkangjanavanich S, Chiewchalermsri C. et al. Increased circulating CRTH2+ Tregs are associated with asthma control and exacerbation. Allergy 2022; 77 (02) 681-685
- 45 Allahverdian S, Harada N, Singhera GK, Knight DA, Dorscheid DR. Secretion of IL-13 by airway epithelial cells enhances epithelial repair via HB-EGF. Am J Respir Cell Mol Biol 2008; 38 (02) 153-160
- 46 Rosa-Rosa L, Zimmermann N, Bernstein JA, Rothenberg ME, Khurana Hershey GK. The R576 IL-4 receptor alpha allele correlates with asthma severity. J Allergy Clin Immunol 1999; 104 (05) 1008-1014
- 47 Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA. The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med 1997; 337 (24) 1720-1725
- 48 Tachdjian R, Mathias C, Al Khatib S. et al. Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. J Exp Med 2009; 206 (10) 2191-2204
- 49 Massoud AH, Charbonnier LM, Lopez D, Pellegrini M, Phipatanakul W, Chatila TA. An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med 2016; 22 (09) 1013-1022
- 50 Wang J, Zhang X, Zhang L. et al. Age-related clinical characteristics, inflammatory features, phenotypes, and treatment response in asthma. J Allergy Clin Immunol Pract 2023; 11 (01) 210-219.e3
- 51 Busse PJ, Birmingham JM, Calatroni A. et al. Effect of aging on sputum inflammation and asthma control. J Allergy Clin Immunol 2017; 139 (06) 1808-1818.e6
- 52 Budde J, Skloot GS. Is aging a “comorbidity” of asthma?. Pulm Pharmacol Ther 2018; 52: 52-56
- 53 Carpentier M, Chappert P, Kuhn C. et al. Extrathymic induction of Foxp3+ regulatory T cells declines with age in a T-cell intrinsic manner. Eur J Immunol 2013; 43 (10) 2598-2604
- 54 McGee HS, Agrawal DK. Naturally occurring and inducible T-regulatory cells modulating immune response in allergic asthma. Am J Respir Crit Care Med 2009; 180 (03) 211-225
- 55 Huang H, Ma Y, Dawicki W, Zhang X, Gordon JR. Comparison of induced versus natural regulatory T cells of the same TCR specificity for induction of tolerance to an environmental antigen. J Immunol 2013; 191 (03) 1136-1143
- 56 Mota-Pinto A, Todo A, Alves V, Santos A, Santos M. Regulatory T cells in elderly patients with asthma. J Investig Allergol Clin Immunol 2011; 21 (03) 199-206
- 57 Birmingham JM, Chesnova B, Wisnivesky JP. et al. The effect of age on T-regulatory cell number and function in patients with asthma. Allergy Asthma Immunol Res 2021; 13 (04) 646-654
- 58 Vale-Pereira S, Todo-Bom A, Geraldes L, Schmidt-Weber C, Akdis CA, Mota-Pinto A. FoxP3, GATA-3 and T-bet expression in elderly asthma. Clin Exp Allergy 2011; 41 (04) 490-496
- 59 Carter AE, Merriam S. Menopause. Med Clin North Am 2023; 107 (02) 199-212
- 60 Triebner K, Johannessen A, Puggini L. et al. Menopause as a predictor of new-onset asthma: a longitudinal Northern European population study. J Allergy Clin Immunol 2016; 137 (01) 50-57.e6
- 61 Troisi RJ, Speizer FE, Willett WC, Trichopoulos D, Rosner B. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. A prospective cohort study. Am J Respir Crit Care Med 2012
- 62 Kesibi D, Rotondi M, Edgell H, Tamim H. The association between age at natural menopause and risk of asthma among postmenopausal women from the Canadian Longitudinal Study on Aging. Menopause 2024; 31 (12) 1069-1077
- 63 Zemp E, Schikowski T, Dratva J, Schindler C, Probst-Hensch N. Asthma and the menopause: a systematic review and meta-analysis. Maturitas 2012; 73 (03) 212-217
- 64 Matulonga-Diakiese B, Courbon D, Fournier A. et al. Risk of asthma onset after natural and surgical menopause: results from the French E3N cohort. Maturitas 2018; 118: 44-50
- 65 Peacock K, Carlson K, Ketvertis KM. Menopause. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025
- 66 Zaibi H, Touil A, Fessi R, Ben Amar J, Aouina H. Asthma in menopausal women: clinical and functional particularities. Tanaffos 2020; 19 (03) 216-222
- 67 Carey MA, Card JW, Bradbury JA. et al. Spontaneous airway hyperresponsiveness in estrogen receptor-α-deficient mice. Am J Respir Crit Care Med 2007; 175 (02) 126-135
- 68 Tai P, Wang J, Jin H. et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol 2008; 214 (02) 456-464
- 69 Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol 2007; 19 (03) 337-343
- 70 GINA Scientific Committee. Global Strategy for Asthma Management and Prevention. 2024 Update. Accessed at: www.ginasthma.org
- 71 Mozo L, Suárez A, Gutiérrez C. Glucocorticoids up-regulate constitutive interleukin-10 production by human monocytes. Clin Exp Allergy 2004; 34 (03) 406-412
- 72 Carmichael J, Paterson IC, Diaz P, Crompton GK, Kay AB, Grant IW. Corticosteroid resistance in chronic asthma. Br Med J (Clin Res Ed) 1981; 282 (6274): 1419-1422
- 73 Haczku A, Alexander A, Brown P. et al. The effect of dexamethasone, cyclosporine, and rapamycin on T-lymphocyte proliferation in vitro: comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma. J Allergy Clin Immunol 1994; 93 (02) 510-519
- 74 Nguyen QT, Kim D, Iamsawat S. et al. Cutting edge: steroid responsiveness in Foxp3+ regulatory T cells determines steroid sensitivity during allergic airway inflammation in mice. J Immunol 2021; 207 (03) 765-770
- 75 Xystrakis E, Kusumakar S, Boswell S. et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 2006; 116 (01) 146-155
- 76 López-Abente J, Benito-Villalvilla C, Jaumont X, Pfister P, Tassinari P, Palomares O. Omalizumab restores the ability of human plasmacytoid dendritic cells to induce Foxp3+Tregs. Eur Respir J 2021; 57 (01) 2000751
- 77 Benito-Villalvilla C, de la Rocha-Muñoz A, López-Abente J. et al. Ligelizumab impairs IgE-binding to plasmacytoid dendritic cells more potently than omalizumab and restores IFN-α production and FOXP3+ Treg generation. Allergy 2023; 78 (04) 1060-1072
- 78 Bergantini L, d'Alessandro M, Cameli P. et al. Regulatory T cell monitoring in severe eosinophilic asthma patients treated with mepolizumab. Scand J Immunol 2021; 94 (01) e13031
- 79 Bergantini L, Pianigiani T, d'Alessandro M. et al. The effect of anti-IL5 monoclonal antibodies on regulatory and effector T cells in severe eosinophilic asthma. Biomed Pharmacother 2023; 166: 115385
- 80 Franceschini D, Paroli M, Francavilla V. et al. PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest 2009; 119 (03) 551-564
- 81 Matsuyama T, Takahashi H, Tada H, Chikamatsu K, Circulating T. Circulating T cell subsets and ILC2s are altered in patients with chronic rhinosinusitis with nasal polyps after dupilumab treatment. Am J Rhinol Allergy 2023; 37 (01) 58-64
- 82 Diver S, Khalfaoui L, Emson C. et al; CASCADE study investigators. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med 2021; 9 (11) 1299-1312
- 83 Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122 (08) 2731-2740
- 84 Rubenfeld GD, Caldwell E, Peabody E. et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353 (16) 1685-1693
- 85 Ranieri VM, Rubenfeld GD, Thompson BT. et al; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307 (23) 2526-2533
- 86 D'Alessio FR, Tsushima K, Aggarwal NR. et al. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest 2009; 119 (10) 2898-2913
- 87 Walter JM, Helmin KA, Abdala-Valencia H, Wunderink RG, Singer BD. Multidimensional assessment of alveolar T cells in critically ill patients. JCI Insight 2018; 3 (17) e123287
- 88 Grant RA, Morales-Nebreda L, Markov NS. et al; NU SCRIPT Study Investigators. Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia. Nature 2021; 590 (7847): 635-641
- 89 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 (01) 35-43
- 90 Fulton RB, Meyerholz DK, Varga SM. Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. J Immunol 2010; 185 (04) 2382-2392
- 91 Loebbermann J, Thornton H, Durant L. et al. Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection. Mucosal Immunol 2012; 5 (02) 161-172
- 92 Cheon IS, Li C, Son YM. et al. Immune signatures underlying post-acute COVID-19 lung sequelae. Sci Immunol 2021; 6 (65) eabk1741
- 93 Narasimhan H, Cheon IS, Qian W. et al. An aberrant immune-epithelial progenitor niche drives viral lung sequelae. Nature 2024; 634 (8035): 961-969
- 94 Betts RJ, Prabhu N, Ho AW. et al. Influenza A virus infection results in a robust, antigen-responsive, and widely disseminated Foxp3+ regulatory T cell response. J Virol 2012; 86 (05) 2817-2825
- 95 Gondek DC, Lu L-F, Quezada SA, Sakaguchi S, Noelle RJ. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 2005; 174 (04) 1783-1786
- 96 de Sousa Palmeira PH, Peixoto RF, Csordas BG. et al. Differential regulatory T cell signature after recovery from mild COVID-19. Front Immunol 2023; 14: 1078922
- 97 Alexander C-M, Tygrett LT, Boyden AW, Wolniak KL, Legge KL, Waldschmidt TJ. T regulatory cells participate in the control of germinal centre reactions. Immunology 2011; 133 (04) 452-468
- 98 León B, Bradley JE, Lund FE, Randall TD, Ballesteros-Tato A. FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun 2014; 5: 3495
- 99 Wing JB, Tekgüç M, Sakaguchi S. Control of germinal center responses by T-follicular regulatory cells. Front Immunol 2018; 9: 1910
- 100 Lu Y, Jiang R, Freyn AW. et al. CD4+ follicular regulatory T cells optimize the influenza virus-specific B cell response. J Exp Med 2021; 218 (03) e20200547
- 101 Kraft ARM, Wlodarczyk MF, Kenney LL, Selin LK. PC61 (anti-CD25) treatment inhibits influenza A virus-expanded regulatory T cells and severe lung pathology during a subsequent heterologous lymphocytic choriomeningitis virus infection. J Virol 2013; 87 (23) 12636-12647
- 102 van der Veeken J, Gonzalez AJ, Cho H. et al. Memory of inflammation in regulatory T cells. Cell 2016; 166 (04) 977-990
- 103 Miragaia RJ, Gomes T, Chomka A. et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity 2019; 50 (02) 493-504.e7
- 104 Brincks EL, Roberts AD, Cookenham T. et al. Antigen-specific memory regulatory CD4+Foxp3+ T cells control memory responses to influenza virus infection. J Immunol 2013; 190 (07) 3438-3446
- 105 Lin P-H, Wong WI, Wang YL. et al. Vaccine-induced antigen-specific regulatory T cells attenuate the antiviral immunity against acute influenza virus infection. Mucosal Immunol 2018; 11 (04) 1239-1253
- 106 Siwicki M, Kubes P. Neutrophils in host defense, healing, and hypersensitivity: dynamic cells within a dynamic host. J Allergy Clin Immunol 2023; 151 (03) 634-655
- 107 Aggarwal A, Baker CS, Evans TW, Haslam PL. G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome. Eur Respir J 2000; 15 (05) 895-901
- 108 Ferretti S, Bonneau O, Dubois GR, Jones CE, Trifilieff A. IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol 2003; 170 (04) 2106-2112
- 109 Wang Y, Ju M, Chen C. et al. Neutrophil-to-lymphocyte ratio as a prognostic marker in acute respiratory distress syndrome patients: a retrospective study. J Thorac Dis 2018; 10 (01) 273-282
- 110 Walter JM, Ren Z, Yacoub T. et al. Multidimensional assessment of the host response in mechanically ventilated patients with suspected pneumonia. Am J Respir Crit Care Med 2019; 199 (10) 1225-1237
- 111 George PM, Reed A, Desai SR. et al. A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae. Sci Transl Med 2022; 14 (671) eabo5795
- 112 Moser EK, Hufford MM, Braciale TJ. Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP3+ regulatory T cell dependent manner. PLoS Pathog 2014; 10 (08) e1004315
- 113 Lewkowicz P, Lewkowicz N, Sasiak A, Tchórzewski H. Lipopolysaccharide-activated CD4+CD25+ T regulatory cells inhibit neutrophil function and promote their apoptosis and death. J Immunol 2006; 177 (10) 7155-7163
- 114 Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor β. J Exp Med 2001; 194 (05) 629-644
- 115 Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A 2007; 104 (49) 19446-19451
- 116 Liu Q, Dwyer GK, Zhao Y. et al. IL-33-mediated IL-13 secretion by ST2+ Tregs controls inflammation after lung injury. JCI Insight 2019 4. 06 -e123919
- 117 Proto JD, Doran AC, Gusarova G. et al. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity 2018; 49 (04) 666-677.e6
- 118 Aggarwal NR, Tsushima K, Eto Y. et al. Immunological priming requires regulatory T cells and IL-10-producing macrophages to accelerate resolution from severe lung inflammation. J Immunol 2014; 192 (09) 4453-4464
- 119 Shi CC, Zhu HY, Li H. et al. Regulating the balance of Th17/Treg cells in gut-lung axis contributed to the therapeutic effect of Houttuynia cordata polysaccharides on H1N1-induced acute lung injury. Int J Biol Macromol 2020; 158: 52-66
- 120 Xie K, Chai YS, Lin SH, Xu F, Wang CJ. Luteolin regulates the differentiation of regulatory T cells and activates IL-10-dependent macrophage polarization against acute lung injury. J Immunol Res 2021; 2021: 8883962
- 121 Chai Y-S, Chen YQ, Lin SH. et al. Curcumin regulates the differentiation of naïve CD4+T cells and activates IL-10 immune modulation against acute lung injury in mice. Biomed Pharmacother 2020; 125: 109946
- 122 Chen YQ, Wang CJ, Xie K. et al. Progranulin improves acute lung injury through regulating the differentiation of regulatory T cells and interleukin-10 immunomodulation to promote macrophage polarization. Mediators Inflamm 2020; 2020: 9704327
- 123 Chen Z, Chen Y, Zhou J, Li Y, Gong C, Wang X. Netrin-1 reduces lung ischemia-reperfusion injury by increasing the proportion of regulatory T cells. J Int Med Res 2020; 48 (06) 300060520926415
- 124 Shah D, Romero F, Stafstrom W, Duong M, Summer R. Extracellular ATP mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2014; 306 (02) L152-L161
- 125 Eckle T, Grenz A, Laucher S, Eltzschig HK. A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice. J Clin Invest 2008; 118 (10) 3301-3315
- 126 Schingnitz U, Hartmann K, Macmanus CF. et al. Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury. J Immunol 2010; 184 (09) 5271-5279
- 127 Eltzschig HK, Sitkovsky MV, Robson SC. Purinergic signaling during inflammation. N Engl J Med 2012; 367 (24) 2322-2333
- 128 Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J Immunol 2006; 177 (10) 6780-6786
- 129 Ehrentraut H, Clambey ET, McNamee EN. et al. CD73+ regulatory T cells contribute to adenosine-mediated resolution of acute lung injury. FASEB J 2013; 27 (06) 2207-2219
- 130 Arpaia N, Green JA, Moltedo B. et al. A distinct function of regulatory T cells in tissue protection. Cell 2015; 162 (05) 1078-1089
- 131 Harb H, Benamar M, Lai PS. et al. Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections. Immunity 2021; 54 (06) 1186-1199.e7
- 132 Kaiser KA, Loffredo LF, Santos-Alexis KL, Ringham OR, Arpaia N. Regulation of the alveolar regenerative niche by amphiregulin-producing regulatory T cells. J Exp Med 2023; 220 (03) e20221462
- 133 Dial CF, Tune MK, Doerschuk CM, Mock JR. Foxp3+ regulatory T cell expression of keratinocyte growth factor enhances lung epithelial proliferation. Am J Respir Cell Mol Biol 2017; 57 (02) 162-173
- 134 Okamoto M, Kuratani A, Okuzaki D. et al. Tff1-expressing Tregs in lung prevent exacerbation of bleomycin-induced pulmonary fibrosis. Front Immunol 2024; 15: 1440918
- 135 Sell S, McKinstry KK, Strutt TM. Mouse models reveal role of T-cytotoxic and T-Reg cells in immune response to influenza: implications for vaccine design. Viruses 2019; 11 (01) 52
- 136 Mock JR, Dial CF, Tune MK. et al. Impact of regulatory T cells on type 2 alveolar epithelial cell transcriptomes during resolution of acute lung injury and contributions of IFN-γ. Am J Respir Cell Mol Biol 2020; 63 (04) 464-477
- 137 D'Alessio FR, Zhong Q, Jenkins J, Moldobaeva A, Wagner EM. Lung angiogenesis requires CD4(+) forkhead homeobox protein-3(+) regulatory T cells. Am J Respir Cell Mol Biol 2015; 52 (05) 603-610
- 138 Morales-Nebreda L, Helmin KA, Torres Acosta MA. et al. Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia. JCI Insight 2021; 6 (06) e141690
- 139 Yu ZX, Ji MS, Yan J. et al. The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome. Crit Care 2015; 19 (01) 82
- 140 Halter S, Aimade L, Barbié M. et al. T regulatory cells activation and distribution are modified in critically ill patients with acute respiratory distress syndrome: a prospective single-centre observational study. Anaesth Crit Care Pain Med 2020; 39 (01) 35-44
- 141 Norton DL, Ceppe A, Tune MK. et al. Bronchoalveolar Tregs are associated with duration of mechanical ventilation in acute respiratory distress syndrome. J Transl Med 2020; 18 (01) 427
- 142 Gonçalves-Pereira MH, Santiago L, Ravetti CG. et al. Dysfunctional phenotype of systemic and pulmonary regulatory T cells associate with lethal COVID-19 cases. Immunology 2023; 168 (04) 684-696
- 143 Adamzik M, Broll J, Steinmann J. et al. An increased alveolar CD4 + CD25 + Foxp3 + T-regulatory cell ratio in acute respiratory distress syndrome is associated with increased 30-day mortality. Intensive Care Med 2013; 39 (10) 1743-1751
- 144 Risso K, Kumar G, Ticchioni M. et al. Early infectious acute respiratory distress syndrome is characterized by activation and proliferation of alveolar T-cells. Eur J Clin Microbiol Infect Dis 2015; 34 (06) 1111-1118
- 145 Gladstone DE, Kim BS, Mooney K, Karaba AH, D'Alessio FR, Regulatory T. Regulatory T cells for treating patients with COVID-19 and acute respiratory distress syndrome: two case reports. Ann Intern Med 2020; 173 (10) 852-853
- 146 Gladstone DE, D'Alessio F, Howard C. et al. Randomized, double-blinded, placebo-controlled trial of allogeneic cord blood T-regulatory cells for treatment of COVID-19 ARDS. Blood Adv 2023; 7 (13) 3075-3079
- 147 Travis WD, Costabel U, Hansell DM. et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188 (06) 733-748
- 148 Ghandikota S, Sharma M, Ediga HH, Madala SK, Jegga AG. Consensus gene co-expression network analysis identifies novel genes associated with severity of fibrotic lung disease. Int J Mol Sci 2022; 23 (10) 5447
- 149 Vassallo R. Viral-induced inflammation in interstitial lung diseases. Semin Respir Infect 2003; 18 (01) 55-60
- 150 Parent RA. ed. Comparative Biology of the Normal Lung. Elsevier; 2015
- 151 Raghu G, Remy-Jardin M, Ryerson CJ. et al. Diagnosis of hypersensitivity pneumonitis in adults. An official ATS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2020; 202 (03) e36-e69
- 152 Cerro Chiang G, Parimon T. Understanding interstitial lung diseases associated with connective tissue disease (CTD-ILD): genetics, cellular pathophysiology, and biologic drivers. Int J Mol Sci 2023; 24 (03) 2405
- 153 Raghu G, Remy-Jardin M, Myers JL. et al; American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2018; 198 (05) e44-e68
- 154 Vuga LJ, Tedrow JR, Pandit KV. et al. C-X-C motif chemokine 13 (CXCL13) is a prognostic biomarker of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014; 189 (08) 966-974
- 155 Rosas IO, Richards TJ, Konishi K. et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med 2008; 5 (04) e93
- 156 Herazo-Maya JD, Sun J, Molyneaux PL. et al. Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study. Lancet Respir Med 2017; 5 (11) 857-868
- 157 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 (205) 205ra136
- 158 Unterman A, Zhao AY, Neumark N. et al. Single-cell profiling reveals immune aberrations in progressive idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2024; 210 (04) 484-496
- 159 Dai X, Yang Z, Zhang W. et al. Identification of diagnostic gene biomarkers related to immune infiltration in patients with idiopathic pulmonary fibrosis based on bioinformatics strategies. Front Med (Lausanne) 2022; 9: 959010
- 160 Bonham CA, Hrusch CL, Blaine KM. et al. T cell co-stimulatory molecules ICOS and CD28 stratify idiopathic pulmonary fibrosis survival. Respir Med X 2019; 1: 100002
- 161 Oldham JM, Huang Y, Bose S. et al. Proteomic biomarkers of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2024; 209 (09) 1111-1120
- 162 Gilani SR, Vuga LJ, Lindell KO. et al. CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis. PLoS One 2010; 5 (01) e8959
- 163 Adegunsoye A, Hrusch CL, Bonham CA. et al. Skewed lung CCR4 to CCR6 CD4+ T cell ratio in idiopathic pulmonary fibrosis is associated with pulmonary function. Front Immunol 2016; 7: 516
- 164 Nuovo GJ, Hagood JS, Magro CM. et al. The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis. Mod Pathol 2012; 25 (03) 416-433
- 165 Yoon YM. et al. Antigenic responses are hallmarks of fibrotic interstitial lung diseases independent of underlying etiologies. 2023. Preprint at https://doi.org/10.1101/2023.05.08.23289640
- 166 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 (12) 1121-1130
- 167 Galati 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 (02) 119-126
- 168 Mendoza N, Casas-Recasens S, Olvera N. et al. Blood immunophenotypes of idiopathic pulmonary fibrosis: relationship with disease severity and progression. Int J Mol Sci 2023; 24 (18) 13832
- 169 Serezani APM, Pascoalino BD, Bazzano JMR. et al. Multiplatform single-cell analysis identifies immune cell types enhanced in pulmonary fibrosis. Am J Respir Cell Mol Biol 2022; 67 (01) 50-60
- 170 Hou Z, Ye Q, Qiu M, Hao Y, Han J, Zeng H. Increased activated regulatory T cells proportion correlate with the severity of idiopathic pulmonary fibrosis. Respir Res 2017; 18 (01) 170
- 171 Reilkoff RA, Peng H, Murray LA. et al. Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-β1-induced pulmonary fibrosis. Am J Respir Crit Care Med 2013; 187 (02) 180-188
- 172 Allan SE, Crome SQ, Crellin NK. et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 2007; 19 (04) 345-354
- 173 Ferreira RC, Simons HZ, Thompson WS. et al. Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity. J Autoimmun 2017; 84: 75-86
- 174 Hotta-Iwamura C, Benck C, Coley WD. et al. Low CD25 on autoreactive Tregs impairs tolerance via low dose IL-2 and antigen delivery. J Autoimmun 2018; 90: 39-48
- 175 Koether K, Besnard V, Sandig H. et al. Autoantibodies are associated with disease progression in idiopathic pulmonary fibrosis. Eur Respir J 2023; 61 (05) 2102381
- 176 Upadhyay V, Yoon YM, Vazquez SE. et al. Phage immunoprecipitation-sequencing reveals CDHR5 autoantibodies in select patients with interstitial lung disease. ACR Open Rheumatol 2024; 6 (09) 568-580
- 177 Zhong B, Zhou JQ, Lyu X. et al. Anti-heat shock protein 70 autoantibodies from patients with idiopathic pulmonary fibrosis epigenetically enhance lung fibroblast apoptosis resistance and Bcl-2 expression. J Immunol 2024; 213 (08) 1150-1156
- 178 Sasai T, Nakashima R, Handa T. et al. Anti-interferon gamma-inducible protein 16 antibodies: identification of a novel autoantigen in idiopathic interstitial pneumonia and its clinical characteristics based on a multicenter cohort study. Clin Immunol 2024; 268: 110372
- 179 Pasterkamp RJ, Peschon JJ, Spriggs MK, Kolodkin AL. Semaphorin 7A promotes axon outgrowth through integrins and MAPKs. Nature 2003; 424 (6947) 398-405
- 180 Czopik AK, Bynoe MS, Palm N, Raine CS, Medzhitov R. Semaphorin 7A is a negative regulator of T cell responses. Immunity 2006; 24 (05) 591-600
- 181 Girard M, Israël-Assayag E, Cormier Y. Impaired function of regulatory T-cells in hypersensitivity pneumonitis. Eur Respir J 2011; 37 (03) 632-639
- 182 Zhao AY, Unterman A, Abu Hussein NS. et al. Single-cell analysis reveals novel immune perturbations in fibrotic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2024; 210 (10) 1252-1266
- 183 de Silva TA, Apte S, Voisey J. et al. Single-cell profiling of cells in the lung of a patient with chronic hypersensitivity pneumonitis reveals inflammatory niche with abundant CD39+ T cells with functional ATPase phenotype: a case study. Int J Mol Sci 2023; 24 (19) 14442
- 184 Egger C, Cannet C, Gérard C. et al. Administration of bleomycin via the oropharyngeal aspiration route leads to sustained lung fibrosis in mice and rats as quantified by UTE-MRI and histology. PLoS One 2013; 8 (05) e63432
- 185 Bivas-Benita M, Zwier R, Junginger HE, Borchard G. Non-invasive pulmonary aerosol delivery in mice by the endotracheal route. Eur J Pharm Biopharm 2005; 61 (03) 214-218
- 186 Mouratis MA, Aidinis V. Modeling pulmonary fibrosis with bleomycin. Curr Opin Pulm Med 2011; 17 (05) 355-361
- 187 Degryse AL, Tanjore H, Xu XC. et al. Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2010; 299 (04) L442-L452
- 188 Barbayianni I, Ninou I, Tzouvelekis A, Aidinis V. Bleomycin revisited: a direct comparison of the intratracheal micro-spraying and the oropharyngeal aspiration routes of bleomycin administration in mice. Front Med (Lausanne) 2018; 5: 269
- 189 Redente EF, Black BP, Backos DS. et al. Persistent, progressive pulmonary fibrosis and epithelial remodeling in mice. Am J Respir Cell Mol Biol 2021; 64 (06) 669-676
- 190 Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther 2014; 349 (02) 209-220
- 191 Kakugawa T, Mukae H, Hayashi T. et al. Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis. Eur Respir J 2004; 24 (01) 57-65
- 192 Schelegle ES, Mansoor JK, Giri S. Pirfenidone attenuates bleomycin-induced changes in pulmonary functions in hamsters. Proc Soc Exp Biol Med 1997; 216 (03) 392-397
- 193 Boveda-Ruiz D, D'Alessandro-Gabazza CN, Toda M. et al. Differential role of regulatory T cells in early and late stages of pulmonary fibrosis. Immunobiology 2013; 218 (02) 245-254
- 194 Chakraborty K, Chatterjee S, Bhattacharyya A. Impact of Treg on other T cell subsets in progression of fibrosis in experimental lung fibrosis. Tissue Cell 2018; 53: 87-92
- 195 Kamio K, Azuma A, Matsuda K. et al. Resolution of bleomycin-induced murine pulmonary fibrosis via a splenic lymphocyte subpopulation. Respir Res 2018; 19 (01) 71
- 196 Birjandi SZ, Palchevskiy V, Xue YY. et al. CD4(+)CD25(hi)Foxp3(+) cells exacerbate bleomycin-induced pulmonary fibrosis. Am J Pathol 2016; 186 (08) 2008-2020
- 197 Glass DS, Grossfeld D, Renna HA. et al. Idiopathic pulmonary fibrosis: current and future treatment. Clin Respir J 2022; 16 (02) 84-96
- 198 d'Alessandro M, Bergantini L, Cameli P. et al. Immunologic responses to antifibrotic treatment in IPF patients. Int Immunopharmacol 2021; 95: 107525
- 199 Kagawa K, Sato S, Koyama K. et al. The lymphocyte-specific protein tyrosine kinase-specific inhibitor A-770041 attenuates lung fibrosis via the suppression of TGF-β production in regulatory T-cells. PLoS One 2022; 17 (10) e0275987
- 200 Xu Y, Lan P, Wang T. The role of immune cells in the pathogenesis of idiopathic pulmonary fibrosis. Medicina (Kaunas) 2023; 59 (11) 1984
- 201 Liu H, Shen J, He C. Advances in idiopathic pulmonary fibrosis diagnosis and treatment. Chin Med J Pulm Crit Care Med 2025; 3 (01) 12-21