The immunopathology of lung fibrosis: amphiregulin-producing pathogenic memory T helper-2 cells control the airway fibrotic responses by inducing eosinophils to secrete osteopontin

  • Kiyoshi HiraharaEmail author
  • Ami Aoki
  • Yuki Morimoto
  • Masahiro Kiuchi
  • Mikiko Okano
  • Toshinori Nakayama


Fibrosis is defined as excessive deposition of the extracellular matrix (ECM) in the parenchyma of various organs, and sometimes leads to irreversible organ malfunction such as idiopathic pulmonary fibrosis (IPF), a fatal disorder of the lung. Chronic inflammatory stimuli induce fibrotic responses in various organs. Various immune cells, including T helper (Th) cells in the lung, protect the host from different harmful particles, including pathogenic microorganisms. However, the dysregulation of the function of these immune cells in the lung sometimes causes inflammatory diseases, such as lung fibrosis. In this review, we will introduce an outline of the cellular and molecular mechanisms underlying the pathogenic fibrotic responses in the lung. We will also introduce the concept of the “Pathogenic Th population disease induction model,” in which unique subpopulations of certain Th cell subsets control the pathology of immune-mediated inflammatory diseases. Finally, we introduce our recent findings, which demonstrate that amphiregulin-producing pathogenic memory Th2 cells control airway fibrosis through the osteopontin produced by inflammatory eosinophils. The identification of this new pathogenic Th cell population supports the concept of “Pathogenic Th population disease induction model”, and will provide novel strategies for treating intractable diseases, including lung fibrosis.


Fibrosis Extracellular matrix (ECM) Asthma “Pathogenic Th population disease induction model” Amphiregulin-producing pathogenic memory Th2 cells Osteopontin Inflammatory eosinophils 



We appreciate all of the members in Department of Immunology, Graduate School of Medicine, Chiba University, Japan.

Funding information

This work was supported by the following grants: Ministry of Education, Culture, Sports, Science and Technology (MEXT Japan) Grants-in-Aid for Scientific Research (S) 26221305, (C) 17K08876; Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from the Japan Agency for Medical Research and Development, AMED (No. JP18ek0410030, JP18ek0410045); AMED-PRIME, AMED (No. JP18gm6110005); AMED-CREST, AMED (No. JP18gm1210003); Mochida Memorial Foundation for Medical and Pharmaceutical Research, The Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care and Takeda Science Foundation.

Compliance with ethical standards

Competing interests

The authors declare that they have no conflict of interest.


  1. 1.
    Wynn TA (2004) Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 4(8):583–594Google Scholar
  2. 2.
    Wick G, Grundtman C, Mayerl C, Wimpissinger TF, Feichtinger J, Zelger B, Sgonc R, Wolfram D (2013) The immunology of fibrosis. Annu Rev Immunol 31:107–135Google Scholar
  3. 3.
    Zuo W, Zhang T, Wu DZ, Guan SP, Liew AA, Yamamoto Y, Wang X, Lim SJ, Vincent M, Lessard M, Crum CP, Xian W, McKeon F (2015) p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration. Nature 517(7536):616–620Google Scholar
  4. 4.
    Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, Tan K, Tan V, Liu FC, Looney MR, Matthay MA, Rock JR, Chapman HA (2015) Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517(7536):621–625Google Scholar
  5. 5.
    Zhang Y, Lee TC, Guillemin B, Yu MC, Rom WN (1993) Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure. J Immunol 150(9):4188–4196Google Scholar
  6. 6.
    Tsukui T, Ueha S, Abe J, Hashimoto S, Shichino S, Shimaoka T, Shand FH, Arakawa Y, Oshima K, Hattori M, Inagaki Y, Tomura M, Matsushima K (2013) Qualitative rather than quantitative changes are hallmarks of fibroblasts in bleomycin-induced pulmonary fibrosis. Am J Pathol 183(3):758–773Google Scholar
  7. 7.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3(5):349–363Google Scholar
  8. 8.
    Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G (2007) The myofibroblast: one function, multiple origins. Am J Pathol 170(6):1807–1816Google Scholar
  9. 9.
    Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A (1994) Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1(1):71–81Google Scholar
  10. 10.
    Herzog EL, Bucala R (2010) Fibrocytes in health and disease. Exp Hematol 38(7):548–556Google Scholar
  11. 11.
    Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM (2004) Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 114(3):438–446Google Scholar
  12. 12.
    Moore BB, Murray L, Das A, Wilke CA, Herrygers AB, Toews GB (2006) The role of CCL12 in the recruitment of fibrocytes and lung fibrosis. Am J Respir Cell Mol Biol 35(2):175–181Google Scholar
  13. 13.
    Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, Margetts PJ, Farkas L, Dobranowski J, Boylan C, O'Byrne PM, Strieter RM, Kolb M (2009) Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 179(7):588–594Google Scholar
  14. 14.
    Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA (2006) Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 103(35):13180–13185Google Scholar
  15. 15.
    Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, Shimokata K, Hasegawa Y (2010) Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 43(2):161–172Google Scholar
  16. 16.
    Stuart T, Satija R (2019) Integrative single-cell analysis. Nat Rev Genet.
  17. 17.
    Montoro DT, Haber AL, Biton M, Vinarsky V, Lin B, Birket SE, Yuan F, Chen S, Leung HM, Villoria J, Rogel N, Burgin G, Tsankov AM, Waghray A, Slyper M, Waldman J, Nguyen L, Dionne D, Rozenblatt-Rosen O, Tata PR, Mou H, Shivaraju M, Bihler H, Mense M, Tearney GJ, Rowe SM, Engelhardt JF, Regev A, Rajagopal J (2018) A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature 560(7718):319–324Google Scholar
  18. 18.
    Cantin AM, Hubbard RC, Crystal RG (1989) Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 139(2):370–372Google Scholar
  19. 19.
    N. Idiopathic Pulmonary Fibrosis clinical research, Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G (2014) Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 370(22):2093–2101Google Scholar
  20. 20.
    Anathy V, Lahue KG, Chapman DG, Chia SB, Casey DT, Aboushousha R, van der Velden JLJ, Elko E, Hoffman SM, McMillan DH, Jones JT, Nolin JD, Abdalla S, Schneider R, Seward DJ, Roberson EC, Liptak MD, Cousins ME, Butnor KJ, Taatjes DJ, Budd RC, Irvin CG, Ho YS, Hakem R, Brown KK, Matsui R, Bachschmid MM, Gomez JL, Kaminski N, van der Vliet A, Janssen-Heininger YMW (2018) Reducing protein oxidation reverses lung fibrosis. Nat Med 24(8):1128–1135Google Scholar
  21. 21.
    Fleischman RW, Baker JR, Thompson GR, Schaeppi UH, Illievski VR, Cooney DA, Davis RD (1971) Bleomycin-induced interstitial pneumonia in dogs. Thorax 26(6):675–682Google Scholar
  22. 22.
    Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3(11):859–868Google Scholar
  23. 23.
    Eferl R, Hasselblatt P, Rath M, Popper H, Zenz R, Komnenovic V, Idarraga MH, Kenner L, Wagner EF (2008) Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Proc Natl Acad Sci U S A 105(30):10525–10530Google Scholar
  24. 24.
    Maurer B, Distler JH, Distler O (2013) The Fra-2 transgenic mouse model of systemic sclerosis. Vasc Pharmacol 58(3):194–201Google Scholar
  25. 25.
    Kanayama M, Xu S, Danzaki K, Gibson JR, Inoue M, Gregory SG, Shinohara ML (2017) Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin. Nat Immunol 18(9):973–984Google Scholar
  26. 26.
    Wernig G, Chen SY, Cui L, Van Neste C, Tsai JM, Kambham N, Vogel H, Natkunam Y, Gilliland DG, Nolan G, Weissman IL (2017) Unifying mechanism for different fibrotic diseases. Proc Natl Acad Sci U S A 114(18):4757–4762Google Scholar
  27. 27.
    Tsujino K, Takeda Y, Arai T, Shintani Y, Inagaki R, Saiga H, Iwasaki T, Tetsumoto S, Jin Y, Ihara S, Minami T, Suzuki M, Nagatomo I, Inoue K, Kida H, Kijima T, Ito M, Kitaichi M, Inoue Y, Tachibana I, Takeda K, Okumura M, Hemler ME, Kumanogoh A (2012) Tetraspanin CD151 protects against pulmonary fibrosis by maintaining epithelial integrity. Am J Respir Crit Care Med 186(2):170–180Google Scholar
  28. 28.
    Povedano JM, Martinez P, Flores JM, Mulero F, Blasco MA (2015) Mice with pulmonary fibrosis driven by telomere dysfunction. Cell Rep 12(2):286–299Google Scholar
  29. 29.
    Gieseck RL 3rd, Wilson MS, Wynn TA (2018) Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol 18(1):62–76Google Scholar
  30. 30.
    Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA, Angelosanto JM, Laidlaw BJ, Yang CY, Sathaliyawala T, Kubota M, Turner D, Diamond JM, Goldrath AW, Farber DL, Collman RG, Wherry EJ, Artis D (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol 12(11):1045–1054Google Scholar
  31. 31.
    Hams E, Armstrong ME, Barlow JL, Saunders SP, Schwartz C, Cooke G, Fahy RJ, Crotty TB, Hirani N, Flynn RJ, Voehringer D, McKenzie AN, Donnelly SC, Fallon PG (2014) IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. Proc Natl Acad Sci U S A 111(1):367–372Google Scholar
  32. 32.
    El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, Konig T, Schleicher U, Koo MS, Kaplan G, Fitzgerald KA, Tuomanen EI, Orme IM, Kanneganti TD, Bogdan C, Wynn TA, Murray PJ (2008) Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9(12):1399–1406Google Scholar
  33. 33.
    Hesse M, Modolell M, La Flamme AC, Schito M, Fuentes JM, Cheever AW, Pearce EJ, Wynn TA (2001) Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J Immunol 167(11):6533–6544Google Scholar
  34. 34.
    Aran D, Looney AP, Liu L, Wu E, Fong V, Hsu A, Chak S, Naikawadi RP, Wolters PJ, Abate AR, Butte AJ, Bhattacharya M (2019) Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol 20(2):163–172Google Scholar
  35. 35.
    Satoh T, Nakagawa K, Sugihara F, Kuwahara R, Ashihara M, Yamane F, Minowa Y, Fukushima K, Ebina I, Yoshioka Y, Kumanogoh A, Akira S (2017) Identification of an atypical monocyte and committed progenitor involved in fibrosis. Nature 541(7635):96–101Google Scholar
  36. 36.
    Nakayama T, Hirahara K, Onodera A, Endo Y, Hosokawa H, Shinoda K, Tumes DJ, Okamoto Y (2017) Th2 cells in health and disease. Annu Rev Immunol 35:53–84Google Scholar
  37. 37.
    Mitson-Salazar A, Yin Y, Wansley DL, Young M, Bolan H, Arceo S, Ho N, Koh C, Milner JD, Stone KD, Wank SA, Prussin C (2016) Hematopoietic prostaglandin D synthase defines a proeosinophilic pathogenic effector human T(H)2 cell subpopulation with enhanced function. J Allergy Clin Immunol 137(3):907–18 e9Google Scholar
  38. 38.
    Wambre E, Bajzik V, DeLong JH, O'Brien K, Nguyen QA, Speake C, Gersuk VH, DeBerg HA, Whalen E, Ni C, Farrington M, Jeong D, Robinson D, Linsley PS, Vickery BP, Kwok WW (2017) A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders. Sci Transl Med 9(401):eaam9171Google Scholar
  39. 39.
    Antonelli A, Ferrari SM, Corrado A, Ferrannini E, Fallahi P (2014) CXCR3, CXCL10 and type 1 diabetes. Cytokine Growth Factor Rev 25(1):57–65Google Scholar
  40. 40.
    Ghoreschi K, Laurence A, Yang XP, Hirahara K, O'Shea JJ (2011) T helper 17 cell heterogeneity and pathogenicity in autoimmune disease. Trends Immunol 32(9):395–401Google Scholar
  41. 41.
    Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, Wu C, Kleinewietfeld M, Kunder S, Hafler DA, Sobel RA, Regev A, Kuchroo VK (2012) Induction and molecular signature of pathogenic TH17 cells. Nat Immunol 13(10):991–999Google Scholar
  42. 42.
    Wang C, Yosef N, Gaublomme J, Wu C, Lee Y, Clish CB, Kaminski J, Xiao S, Horste GMZ, Pawlak M, Kishi Y, Joller N, Karwacz K, Zhu C, Ordovas-Montanes M, Madi A, Wortman I, Miyazaki T, Sobel RA, Park H, Regev A, Kuchroo VK (2015) CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163(6):1413–1427Google Scholar
  43. 43.
    Aschenbrenner D, Foglierini M, Jarrossay D, Hu D, Weiner HL, Kuchroo VK, Lanzavecchia A, Notarbartolo S, Sallusto F (2018) An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells. Nat Immunol 19(10):1126–1136Google Scholar
  44. 44.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23(5):479–490Google Scholar
  45. 45.
    Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L, Bouche G, Girard JP (2007) IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci U S A 104(1):282–287Google Scholar
  46. 46.
    Keller M, Ruegg A, Werner S, Beer HD (2008) Active caspase-1 is a regulator of unconventional protein secretion. Cell 132(5):818–831Google Scholar
  47. 47.
    Cayrol C, Girard JP (2009) The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci U S A 106(22):9021–9026Google Scholar
  48. 48.
    Cayrol C, Girard JP (2014) IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol 31:31–37Google Scholar
  49. 49.
    Moussion C, Ortega N, Girard JP (2008) The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One 3(10):e3331Google Scholar
  50. 50.
    Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, Girard JP (2012) Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain. J Immunol 188(7):3488–3495Google Scholar
  51. 51.
    Liew FY, Girard JP, Turnquist HR (2016) Interleukin-33 in health and disease. Nat Rev Immunol 16(11):676–689Google Scholar
  52. 52.
    Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H, Williams C, Hui J, Beilby J, Warrington NM, James A, Palmer LJ, Koppelman GH, Heinzmann A, Krueger M, Boezen HM, Wheatley A, Altmuller J, Shin HD, Uh ST, Cheong HS, Jonsdottir B, Gislason D, Park CS, Rasmussen LM, Porsbjerg C, Hansen JW, Backer V, Werge T, Janson C, Jonsson UB, Ng MC, Chan J, So WY, Ma R, Shah SH, Granger CB, Quyyumi AA, Levey AI, Vaccarino V, Reilly MP, Rader DJ, Williams MJ, van Rij AM, Jones GT, Trabetti E, Malerba G, Pignatti PF, Boner A, Pescollderungg L, Girelli D, Olivieri O, Martinelli N, Ludviksson BR, Ludviksdottir D, Eyjolfsson GI, Arnar D, Thorgeirsson G, Deichmann K, Thompson PJ, Wjst M, Hall IP, Postma DS, Gislason T, Gulcher J, Kong A, Jonsdottir I, Thorsteinsdottir U, Stefansson K (2009) Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 41(3):342–347Google Scholar
  53. 53.
    Savenije OE, Mahachie John JM, Granell R, Kerkhof M, Dijk FN, de Jongste JC, Smit HA, Brunekreef B, Postma DS, Van Steen K, Henderson J, Koppelman GH (2014) Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood. J Allergy Clin Immunol 134(1):170–177Google Scholar
  54. 54.
    Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H (2008) A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol 121(6):1484–1490Google Scholar
  55. 55.
    Klein Wolterink RG, Serafini N, van Nimwegen M, Vosshenrich CA, de Bruijn MJ, Fonseca Pereira D, Veiga Fernandes H, Hendriks RW, Di Santo JP (2013) Essential, dose-dependent role for the transcription factor Gata3 in the development of IL-5+ and IL-13+ type 2 innate lymphoid cells. Proc Natl Acad Sci U S A 110(25):10240–10245Google Scholar
  56. 56.
    Allakhverdi Z, Smith DE, Comeau MR, Delespesse G (2007) Cutting edge: the ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J Immunol 179(4):2051–2054Google Scholar
  57. 57.
    Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, Furusawa J, Ohtani M, Fujii H, Koyasu S (2010) Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature 463(7280):540–544Google Scholar
  58. 58.
    Endo Y, Hirahara K, Iinuma T, Shinoda K, Tumes DJ, Asou HK, Matsugae N, Obata-Ninomiya K, Yamamoto H, Motohashi S, Oboki K, Nakae S, Saito H, Okamoto Y, Nakayama T (2015) The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity 42(2):294–308Google Scholar
  59. 59.
    Shinoda K, Hirahara K, Iinuma T, Ichikawa T, Suzuki AS, Sugaya K, Tumes DJ, Yamamoto H, Hara T, Tani-Ichi S, Ikuta K, Okamoto Y, Nakayama T (2016) Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation. Proc Natl Acad Sci U S A 113(20):E2842–E2851Google Scholar
  60. 60.
    Kuroda E, Ozasa K, Temizoz B, Ohata K, Koo CX, Kanuma T, Kusakabe T, Kobari S, Horie M, Morimoto Y, Nakajima S, Kabashima K, Ziegler SF, Iwakura Y, Ise W, Kurosaki T, Nagatake T, Kunisawa J, Takemura N, Uematsu S, Hayashi M, Aoshi T, Kobiyama K, Coban C, Ishii KJ (2016) Inhaled fine particles induce alveolar macrophage death and interleukin-1alpha release to promote inducible bronchus-associated lymphoid tissue formation. Immunity 45(6):1299–1310Google Scholar
  61. 61.
    Denton AE, Innocentin S, Carr EJ, Bradford BM, Lafouresse F, Mabbott NA, Morbe U, Ludewig B, Groom JR, Good-Jacobson KL, Linterman MA (2019) Type I interferon induces CXCL13 to support ectopic germinal center formation. J Exp Med 216:621–637Google Scholar
  62. 62.
    Randall TD (2010) Bronchus-associated lymphoid tissue (BALT) structure and function. Adv Immunol 107:187–241Google Scholar
  63. 63.
    Shinoda K, Hirahara K, Nakayama T (2017) Maintenance of pathogenic Th2 cells in allergic disorders. Allergol Int 66(3):369–376Google Scholar
  64. 64.
    Moyron-Quiroz JE, Rangel-Moreno J, Hartson L, Kusser K, Tighe MP, Klonowski KD, Lefrancois L, Cauley LS, Harmsen AG, Lund FE, Randall TD (2006) Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity 25(4):643–654Google Scholar
  65. 65.
    Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401(6754):708–712Google Scholar
  66. 66.
    Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, Carbone FR (2009) Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 10(5):524–530Google Scholar
  67. 67.
    Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22:745–763Google Scholar
  68. 68.
    Mueller SN, Gebhardt T, Carbone FR, Heath WR (2013) Memory T cell subsets, migration patterns, and tissue residence. Annu Rev Immunol 31:137–161Google Scholar
  69. 69.
    Turner DL, Bickham KL, Thome JJ, Kim CY, D'Ovidio F, Wherry EJ, Farber DL (2014) Lung niches for the generation and maintenance of tissue-resident memory T cells. Mucosal Immunol 7(3):501–510Google Scholar
  70. 70.
    Koelle DM, Schomogyi M, Corey L (2000) Antigen-specific T cells localize to the uterine cervix in women with genital herpes simplex virus type 2 infection. J Infect Dis 182(3):662–670Google Scholar
  71. 71.
    Mackay LK, Stock AT, Ma JZ, Jones CM, Kent SJ, Mueller SN, Heath WR, Carbone FR, Gebhardt T (2012) Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc Natl Acad Sci U S A 109(18):7037–7042Google Scholar
  72. 72.
    Teijaro JR, Turner D, Pham Q, Wherry EJ, Lefrancois L, Farber DL (2011) Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J Immunol 187(11):5510–5514Google Scholar
  73. 73.
    Hondowicz BD, An D, Schenkel JM, Kim KS, Steach HR, Krishnamurty AT, Keitany GJ, Garza EN, Fraser KA, Moon JJ, Altemeier WA, Masopust D, Pepper M (2016) Interleukin-2-dependent allergen-specific tissue-resident memory cells drive asthma. Immunity 44(1):155–166Google Scholar
  74. 74.
    Han SJ, Glatman Zaretsky A, Andrade-Oliveira V, Collins N, Dzutsev A, Shaik J, Morais da Fonseca D, Harrison OJ, Tamoutounour S, Byrd AL, Smelkinson M, Bouladoux N, Bliska JB, Brenchley JM, Brodsky IE, Belkaid Y (2017) White adipose tissue is a reservoir for memory T cells and promotes protective memory responses to infection. Immunity 47(6):1154–1168 e6Google Scholar
  75. 75.
    Russell RJ, Brightling C (2017) Pathogenesis of asthma: implications for precision medicine. Clin Sci (Lond) 131(14):1723–1735Google Scholar
  76. 76.
    ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF, Bel EH (2001) Factors associated with persistent airflow limitation in severe asthma. Am J Respir Crit Care Med 164(5):744–748Google Scholar
  77. 77.
    Vannella KM, Ramalingam TR, Borthwick LA, Barron L, Hart KM, Thompson RW, Kindrachuk KN, Cheever AW, White S, Budelsky AL, Comeau MR, Smith DE, Wynn TA (2016) Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis. Sci Transl Med 8(337):337ra65Google Scholar
  78. 78.
    Rothenberg ME, Hogan SP (2006) The eosinophil. Annu Rev Immunol 24:147–174Google Scholar
  79. 79.
    Humbles AA, Lloyd CM, McMillan SJ, Friend DS, Xanthou G, McKenna EE, Ghiran S, Gerard NP, Yu C, Orkin SH, Gerard C (2004) A critical role for eosinophils in allergic airways remodeling. Science 305(5691):1776–1779Google Scholar
  80. 80.
    Rosenberg HF, Dyer KD, Foster PS (2013) Eosinophils: changing perspectives in health and disease. Nat Rev Immunol 13(1):9–22Google Scholar
  81. 81.
    Stoll S, Garner W, Elder J (1997) Heparin-binding ligands mediate autocrine epidermal growth factor receptor activation in skin organ culture. J Clin Invest 100(5):1271–1281Google Scholar
  82. 82.
    Okumura S, Sagara H, Fukuda T, Saito H, Okayama Y (2005) FcepsilonRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells. J Allergy Clin Immunol 115(2):272–279Google Scholar
  83. 83.
    Zaiss DM, Gause WC, Osborne LC, Artis D (2015) Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42(2):216–226Google Scholar
  84. 84.
    Ito M, Komai K, Mise-Omata S, Iizuka-Koga M, Noguchi Y, Kondo T, Sakai R, Matsuo K, Nakayama T, Yoshie O, Nakatsukasa H, Chikuma S, Shichita T, Yoshimura A (2019) Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 565(7738):246–250Google Scholar
  85. 85.
    Zaiss DM, Yang L, Shah PR, Kobie JJ, Urban JF, Mosmann TR (2006) Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science 314(5806):1746Google Scholar
  86. 86.
    Al-Muhsen S, Johnson JR, Hamid Q (2011) Remodeling in asthma. J Allergy Clin Immunol 128(3):451–462 quiz 463-4 Google Scholar
  87. 87.
    Denhardt DT, Noda M, O'Regan AW, Pavlin D, Berman JS (2001) Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest 107(9):1055–1061Google Scholar
  88. 88.
    Sabo-Attwood T, Ramos-Nino ME, Eugenia-Ariza M, Macpherson MB, Butnor KJ, Vacek PC, McGee SP, Clark JC, Steele C, Mossman BT (2011) Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis. Am J Pathol 178(5):1975–1985Google Scholar
  89. 89.
    Nakayama T, Yoshikawa M, Asaka D, Okushi T, Matsuwaki Y, Otori N, Hama T, Moriyama H (2011) Mucosal eosinophilia and recurrence of nasal polyps - new classification of chronic rhinosinusitis. Rhinology 49(4):392–396Google Scholar
  90. 90.
    Hamilos DL (2015) Drivers of chronic rhinosinusitis: inflammation versus infection. J Allergy Clin Immunol 136(6):1454–1459Google Scholar
  91. 91.
    Kobayashi Y, Asako M, Ooka H, Kanda A, Tomoda K, Yasuba H (2015) Residual exhaled nitric oxide elevation in asthmatics is associated with eosinophilic chronic rhinosinusitis. J Asthma 52(10):1060–1064Google Scholar
  92. 92.
    Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR, Investigators IT (2014) Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 370(22):2071–2082Google Scholar
  93. 93.
    Fisher M, Nathan SD, Hill C, Marshall J, Dejonckheere F, Thuresson PO, Maher TM (2017) Predicting life expectancy for pirfenidone in idiopathic pulmonary fibrosis. J Manag Care Spec Pharm 23(3-b Suppl):S17–S24Google Scholar
  94. 94.
    Brunnemer E, Walscher J, Tenenbaum S, Hausmanns J, Schulze K, Seiter M, Heussel CP, Warth A, Herth FJF, Kreuter M (2018) Real-world experience with nintedanib in patients with idiopathic pulmonary fibrosis. Respiration 95(5):301–309Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Kiyoshi Hirahara
    • 1
    • 2
    Email author
  • Ami Aoki
    • 1
  • Yuki Morimoto
    • 1
  • Masahiro Kiuchi
    • 1
  • Mikiko Okano
    • 1
  • Toshinori Nakayama
    • 1
    • 3
  1. 1.Department of ImmunologyGraduate School of Medicine, Chiba UniversityChibaJapan
  2. 2.AMED-PRIME, AMEDChibaJapan
  3. 3.AMED-CREST, AMEDChibaJapan

Personalised recommendations