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ILC2s in infectious diseases and organ-specific fibrosis

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Abstract

Type 2 immune responses evolved to provide host protection against parasitic infections and to support the repair of infection-induced tissue injury. However, persistent chronic organ damage can result in dysregulated production of critical type 2 cytokines supporting tissue remodeling and fibrosis development. Recently, group 2 innate lymphoid cells (ILC2s) were newly described as central innate mediators of type 2 responses. In particular, by secretion of the cytokines IL-5, IL-9, and IL-13 and the growth factor amphiregulin in response to the release of tissue-derived alarmins, ILC2s have been shown to substantially contribute to both the dismissal of metazoan parasites and the repair of infection-dependent or sterile tissue damage. Conversely, cytokine production by ILC2s emerged as a driving force for tissue remodeling and excessive fibrosis in several organ systems including the lung, liver, and skin. In this review, we discuss how ILC2s are specifically implicated in the body’s immune response to different pathogenic infections and how dysregulated ILC2s may promote organ-specific fibrosis.

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References

  1. Diefenbach A, Colonna M, Koyasu S (2014) Development, differentiation, and diversity of innate lymphoid cells. Immunity 41(3):354–365. https://doi.org/10.1016/j.immuni.2014.09.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. McKenzie AN, Spits H, Eberl G (2014) Innate lymphoid cells in inflammation and immunity. Immunity 41(3):366–374. https://doi.org/10.1016/j.immuni.2014.09.006

    Article  PubMed  CAS  Google Scholar 

  3. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, Menon S, Clifford T, Hunte B, Lesley R, Muchamuel T, Hurst SD, Zurawski G, Leach MW, Gorman DM, Rennick DM (2001) IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15(6):985–995

    Article  PubMed  CAS  Google Scholar 

  4. Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T, Kwan S, Menon S, Seymour B, Jackson C, Kung TT, Brieland JK, Zurawski SM, Chapman RW, Zurawski G, Coffman RL (2002) New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol 169(1):443–453

    Article  PubMed  CAS  Google Scholar 

  5. Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR, McIlgorm A, Jolin HE, McKenzie AN (2006) Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med 203(4):1105–1116. https://doi.org/10.1084/jem.20051615

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 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):540–544. https://doi.org/10.1038/nature08636

    Article  PubMed  CAS  Google Scholar 

  7. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie AN (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464(7293):1367–1370. https://doi.org/10.1038/nature08900

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Price AE, Liang HE, Sullivan BM, Reinhardt RL, Eisley CJ, Erle DJ, Locksley RM (2010) Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A 107(25):11489–11494. https://doi.org/10.1073/pnas.1003988107

    Article  PubMed  PubMed Central  Google Scholar 

  9. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, Powrie F, Vivier E (2013) Innate lymphoid cells—a proposal for uniform nomenclature. Nat Rev Immunol 13(2):145–149. https://doi.org/10.1038/nri3365

    Article  PubMed  CAS  Google Scholar 

  10. 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):1045–1054. https://doi.org/10.1031/ni.2131

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Pelly VS, Kannan Y, Coomes SM, Entwistle LJ, Ruckerl D, Seddon B, MacDonald AS, McKenzie A, Wilson MS (2016) IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection. Mucosal Immunol 9(6):1407–1417. https://doi.org/10.1038/mi.2016.4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Seehus CR, Kadavallore A, Torre B, Yeckes AR, Wang Y, Tang J, Kaye J (2017) Alternative activation generates IL-10 producing type 2 innate lymphoid cells. Nat Commun 8(1):1900. https://doi.org/10.1038/s41467-017-02023-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Halim TY, MacLaren A, Romanish MT, Gold MJ, McNagny KM, Takei F (2012) Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity 37(3):463–474. https://doi.org/10.1016/j.immuni.2012.06.012

    Article  PubMed  CAS  Google Scholar 

  14. Wong SH, Walker JA, Jolin HE, Drynan LF, Hams E, Camelo A, Barlow JL, Neill DR, Panova V, Koch U, Radtke F, Hardman CS, Hwang YY, Fallon PG, McKenzie AN (2012) Transcription factor RORalpha is critical for nuocyte development. Nat Immunol 13(3):229–236. https://doi.org/10.1038/ni.2208

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Hoyler T, Klose CS, Souabni A, Turqueti-Neves A, Pfeifer D, Rawlins EL, Voehringer D, Busslinger M, Diefenbach A (2012) The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37(4):634–648. https://doi.org/10.1016/j.immuni.2012.06.020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Spooner CJ, Lesch J, Yan D, Khan AA, Abbas A, Ramirez-Carrozzi V, Zhou M, Soriano R, Eastham-Anderson J, Diehl L, Lee WP, Modrusan Z, Pappu R, Xu M, DeVoss J, Singh H (2013) Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1. Nat Immunol 14(12):1229–1236. https://doi.org/10.1038/ni.2743

    Article  PubMed  CAS  Google Scholar 

  17. Yu Y, Wang C, Clare S, Wang J, Lee SC, Brandt C, Burke S, Lu L, He D, Jenkins NA, Copeland NG, Dougan G, Liu P (2015) The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development. J Exp Med 212(6):865–874. https://doi.org/10.1084/jem.20142318

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Walker JA, Oliphant CJ, Englezakis A, Yu Y, Clare S, Rodewald HR, Belz G, Liu P, Fallon PG, McKenzie AN (2015) Bcl11b is essential for group 2 innate lymphoid cell development. J Exp Med 212(6):875–882. https://doi.org/10.1084/jem.20142224

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, Hepworth MR, Van Voorhees AS, Comeau MR, Artis D (2013) TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med 5(170):170ra116. https://doi.org/10.1126/scitranslmed.3005374

    Article  CAS  Google Scholar 

  20. Xue L, Salimi M, Panse I, Mjosberg JM, McKenzie AN, Spits H, Klenerman P, Ogg G (2014) Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J Allergy Clin Immunol 133(4):1184–1194. https://doi.org/10.1016/j.jaci.2013.10.056

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Doherty TA, Khorram N, Lund S, Mehta AK, Croft M, Broide DH (2013) Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J Allergy Clin Immunol 132(1):205–213. https://doi.org/10.1016/j.jaci.2013.03.048

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Klose CSN, Mahlakoiv T, Moeller JB, Rankin LC, Flamar AL, Kabata H, Monticelli LA, Moriyama S, Putzel GG, Rakhilin N, Shen X, Kostenis E, Konig GM, Senda T, Carpenter D, Farber DL, Artis D (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549(7671):282–286. https://doi.org/10.1038/nature23676

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Cardoso V, Chesne J, Ribeiro H, Garcia-Cassani B, Carvalho T, Bouchery T, Shah K, Barbosa-Morais NL, Harris N, Veiga-Fernandes H (2017) Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549(7671):277–281. https://doi.org/10.1038/nature23469

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Wallrapp A, Riesenfeld SJ, Burkett PR, Abdulnour RE, Nyman J, Dionne D, Hofree M, Cuoco MS, Rodman C, Farouq D, Haas BJ, Tickle TL, Trombetta JJ, Baral P, Klose CSN, Mahlakoiv T, Artis D, Rozenblatt-Rosen O, Chiu IM, Levy BD, Kowalczyk MS, Regev A, Kuchroo VK (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549(7672):351–356. https://doi.org/10.1038/nature24029

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Maazi H, Patel N, Sankaranarayanan I, Suzuki Y, Rigas D, Soroosh P, Freeman GJ, Sharpe AH, Akbari O (2015) ICOS: ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity. Immunity 42(3):538–551. https://doi.org/10.1016/j.immuni.2015.02.007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Paclik D, Stehle C, Lahmann A, Hutloff A, Romagnani C (2015) ICOS regulates the pool of group 2 innate lymphoid cells under homeostatic and inflammatory conditions in mice. Eur J Immunol 45(10):2766–2772. https://doi.org/10.1002/eji.201545635

    Article  PubMed  CAS  Google Scholar 

  27. Duerr CU, McCarthy CD, Mindt BC, Rubio M, Meli AP, Pothlichet J, Eva MM, Gauchat JF, Qureshi ST, Mazer BD, Mossman KL, Malo D, Gamero AM, Vidal SM, King IL, Sarfati M, Fritz JH (2016) Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells. Nat Immunol 17(1):65–75. https://doi.org/10.1038/ni.3308

    Article  PubMed  CAS  Google Scholar 

  28. Moro K, Kabata H, Tanabe M, Koga S, Takeno N, Mochizuki M, Fukunaga K, Asano K, Betsuyaku T, Koyasu S (2016) Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat Immunol 17(1):76–86. https://doi.org/10.1038/ni.3309

    Article  PubMed  CAS  Google Scholar 

  29. McHedlidze T, Kindermann M, Neves AT, Voehringer D, Neurath MF, Wirtz S (2016) IL-27 suppresses type 2 immune responses in vivo via direct effects on group 2 innate lymphoid cells. Mucosal Immunol 9(6):1384–1394. https://doi.org/10.1038/mi.2016.20

    Article  PubMed  CAS  Google Scholar 

  30. Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, Huang LC, Johnson D, Scanlon ST, McKenzie AN, Fallon PG, Ogg GS (2013) A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med 210(13):2939–2950. https://doi.org/10.1084/jem.20130351

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Taylor S, Huang Y, Mallett G, Stathopoulou C, Felizardo TC, Sun MA, Martin EL, Zhu N, Woodward EL, Elias MS, Scott J, Reynolds NJ, Paul WE, Fowler DH, Amarnath S (2017) PD-1 regulates KLRG1(+) group 2 innate lymphoid cells. J Exp Med 214(6):1663–1678. https://doi.org/10.1084/jem.20161653

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Filbey K, Bouchery T, Le Gros G (2017) The role of ILC2 in hookworm infection. Parasite Immunol 40. https://doi.org/10.1111/pim.12429

  33. Mukai K, Karasuyama H, Kabashima K, Kubo M, Galli SJ (2017) Differences in the importance of mast cells, basophils, IgE, and IgG versus that of CD4(+) T cells and ILC2 cells in primary and secondary immunity to Strongyloides venezuelensis. Infect Immun 85(5):e00053–e00017. https://doi.org/10.1128/IAI.00053-17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Hung LY, Lewkowich IP, Dawson LA, Downey J, Yang Y, Smith DE, Herbert DR (2013) IL-33 drives biphasic IL-13 production for noncanonical type 2 immunity against hookworms. Proc Natl Acad Sci U S A 110(1):282–287. https://doi.org/10.1073/pnas.1206587110

    Article  PubMed  Google Scholar 

  35. Oliphant CJ, Hwang YY, Walker JA, Salimi M, Wong SH, Brewer JM, Englezakis A, Barlow JL, Hams E, Scanlon ST, Ogg GS, Fallon PG, McKenzie AN (2014) MHCII-mediated dialog between group 2 innate lymphoid cells and CD4(+) T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41(2):283–295. https://doi.org/10.1016/j.immuni.2014.06.016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Angkasekwinai P, Sodthawon W, Jeerawattanawart S, Hansakon A, Pattanapanyasat K, Wang YH (2017) ILC2s activated by IL-25 promote antigen-specific Th2 and Th9 functions that contribute to the control of Trichinella spiralis infection. PLoS One 12(9):e0184684. https://doi.org/10.1371/journal.pone.0184684

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Pelly VS, Kannan Y, Coomes SM, Entwistle LJ, Ruckerl D, Seddon B, MacDonald AS, McKenzie A, Wilson MS (2016) IL-4-producing ILC2s are required for the differentiation of TH2 cells following Heligmosomoides polygyrus infection. Mucosal Immunol 9:1407–1417. https://doi.org/10.1038/mi.2016.4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. von Moltke J, Ji M, Liang HE, Locksley RM (2016) Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529(7585):221–225. https://doi.org/10.1038/nature16161

    Article  CAS  Google Scholar 

  39. Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, Cesses P, Garnier L, Pouzolles M, Brulin B, Bruschi M, Harcus Y, Zimmermann VS, Taylor N, Maizels RM, Jay P (2016) Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529(7585):226–230. https://doi.org/10.1038/nature16527

    Article  PubMed  CAS  Google Scholar 

  40. Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV, Gallini CA, Redding K, Margolskee RF, Osborne LC, Artis D, Garrett WS (2016) Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351(6279):1329–1333. https://doi.org/10.1126/science.aaf1648

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Haber AL, Biton M, Rogel N, Herbst RH, Shekhar K, Smillie C, Burgin G, Delorey TM, Howitt MR, Katz Y, Tirosh I, Beyaz S, Dionne D, Zhang M, Raychowdhury R, Garrett WS, Rozenblatt-Rosen O, Shi HN, Yilmaz O, Xavier RJ, Regev A (2017) A single-cell survey of the small intestinal epithelium. Nature 551(7680):333–339. https://doi.org/10.1038/nature24489

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Shimokawa C, Kanaya T, Hachisuka M, Ishiwata K, Hisaeda H, Kurashima Y, Kiyono H, Yoshimoto T, Kaisho T, Ohno H (2017) Mast cells are crucial for induction of group 2 innate lymphoid cells and clearance of helminth infections. Immunity 46(5):863–874 e864. https://doi.org/10.1016/j.immuni.2017.04.017

    Article  PubMed  CAS  Google Scholar 

  43. Osbourn M, Soares DC, Vacca F, Cohen ES, Scott IC, Gregory WF, Smyth DJ, Toivakka M, Kemter AM, le Bihan T, Wear M, Hoving D, Filbey KJ, Hewitson JP, Henderson H, Gonzalez-Ciscar A, Errington C, Vermeren S, Astier AL, Wallace WA, Schwarze J, Ivens AC, Maizels RM, McSorley HJ (2017) HpARI protein secreted by a helminth parasite suppresses interleukin-33. Immunity 47 (4):739–751 e735. doi:https://doi.org/10.1016/j.immuni.2017.09.015

  44. Zaiss DMW, Gause WC, Osborne LC, Artis D (2015) Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42(2):216–226. https://doi.org/10.1016/j.immuni.2015.01.020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Rath M, Muller I, Kropf P, Closs EI, Munder M (2014) Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol 5:532. https://doi.org/10.3389/fimmu.2014.00532

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Monticelli LA, Buck MD, Flamar AL, Saenz SA, Tait Wojno ED, Yudanin NA, Osborne LC, Hepworth MR, Tran SV, Rodewald HR, Shah H, Cross JR, Diamond JM, Cantu E, Christie JD, Pearce EL, Artis D (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17(6):656–665. https://doi.org/10.1038/ni.3421

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Turner JE, Morrison PJ, Wilhelm C, Wilson M, Ahlfors H, Renauld JC, Panzer U, Helmby H, Stockinger B (2013) IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J Exp Med 210(13):2951–2965. https://doi.org/10.1084/jem.20130071

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Daly CM, Mayrhofer G, Dent LA (1999) Trapping and immobilization of Nippostrongylus brasiliensis larvae at the site of inoculation in primary infections of interleukin-5 transgenic mice. Infect Immun 67(10):5315–5323

    PubMed  PubMed Central  CAS  Google Scholar 

  49. Rak GD, Osborne LC, Siracusa MC, Kim BS, Wang K, Bayat A, Artis D, Volk SW (2016) IL-33-dependent group 2 innate lymphoid cells promote cutaneous wound healing. The Journal of investigative dermatology 136(2):487–496. https://doi.org/10.1038/JID.2015.406

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Chang YJ, Kim HY, Albacker LA, Baumgarth N, McKenzie AN, Smith DE, Dekruyff RH, Umetsu DT (2011) Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12(7):631–638. https://doi.org/10.1038/ni.2045

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Gorski SA, Hahn YS, Braciale TJ (2013) Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. PLoS Pathog 9(9):e1003615. https://doi.org/10.1371/journal.ppat.1003615

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Silver JS, Kearley J, Copenhaver AM, Sanden C, Mori M, Yu L, Pritchard GH, Berlin AA, Hunter CA, Bowler R, Erjefalt JS, Kolbeck R, Humbles AA (2016) Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. Nat Immunol 17(6):626–635. https://doi.org/10.1038/ni.3443

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Jha A, Jarvis H, Fraser C, Openshaw PJM (2016) Respiratory syncytial virus. In: Hui DS, Rossi GA, Johnston SL (eds) SARS, MERS and other viral lung infections. Wellcome Trust-Funded Monographs and Book Chapters, Sheffield

    Google Scholar 

  54. Stier MT, Bloodworth MH, Toki S, Newcomb DC, Goleniewska K, Boyd KL, Quitalig M, Hotard AL, Moore ML, Hartert TV, Zhou B, McKenzie AN, Peebles RS Jr (2016) Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. J Allergy Clin Immunol 138(3):814–824 e811. https://doi.org/10.1016/j.jaci.2016.01.050

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Zeng S, Wu J, Liu J, Qi F, Liu B (2015) IL-33 receptor (ST2) signalling is important for regulation of Th2-mediated airway inflammation in a murine model of acute respiratory syncytial virus infection. Scand J Immunol 81(6):494–501. https://doi.org/10.1111/sji.12284

    Article  PubMed  CAS  Google Scholar 

  56. Saravia J, You D, Shrestha B, Jaligama S, Siefker D, Lee GI, Harding JN, Jones TL, Rovnaghi C, Bagga B, DeVincenzo JP, Cormier SA (2015) Respiratory syncytial virus disease is mediated by age-variable IL-33. PLoS Pathog 11(10):e1005217. https://doi.org/10.1371/journal.ppat.1005217

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Coleman L, Laing IA, Bosco A (2016) Rhinovirus-induced asthma exacerbations and risk populations. Curr Opin Allergy Clin Immunol 16(2):179–185. https://doi.org/10.1097/ACI.0000000000000245

    Article  PubMed  CAS  Google Scholar 

  58. Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B, Fokkens WJ, Cupedo T, Spits H (2011) Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol 12(11):1055–1062. https://doi.org/10.1038/ni.2104

    Article  PubMed  CAS  Google Scholar 

  59. Hong JY, Bentley JK, Chung Y, Lei J, Steenrod JM, Chen Q, Sajjan US, Hershenson MB (2014) Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells. J Allergy Clin Immunol 134(2):429–439. https://doi.org/10.1016/j.jaci.2014.04.020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Jackson DJ, Makrinioti H, Rana BM, Shamji BW, Trujillo-Torralbo MB, Footitt J, Jerico D-R, Telcian AG, Nikonova A, Zhu J, Aniscenko J, Gogsadze L, Bakhsoliani E, Traub S, Dhariwal J, Porter J, Hunt D, Hunt T, Hunt T, Stanciu LA, Khaitov M, Bartlett NW, Edwards MR, Kon OM, Mallia P, Papadopoulos NG, Akdis CA, Westwick J, Edwards MJ, Cousins DJ, Walton RP, Johnston SL (2014) IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo. Am J Respir Crit Care Med 190(12):1373–1382. https://doi.org/10.1164/rccm.201406-1039OC

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Han M, Rajput C, Hong JY, Lei J, Hinde JL, Wu Q, Bentley JK, Hershenson MB (2017) The innate cytokines IL-25, IL-33, and TSLP cooperate in the induction of type 2 innate lymphoid cell expansion and mucous metaplasia in rhinovirus-infected immature mice. J Immunol 199(4):1308–1318. https://doi.org/10.4049/jimmunol.1700216

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Saluzzo S, Gorki AD, Rana BMJ, Martins R, Scanlon S, Starkl P, Lakovits K, Hladik A, Korosec A, Sharif O, Warszawska JM, Jolin H, Mesteri I, McKenzie ANJ, Knapp S (2017) First-breath-induced type 2 pathways shape the lung immune environment. Cell Rep 18(8):1893–1905. https://doi.org/10.1016/j.celrep.2017.01.071

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Monin L, Griffiths KL, Lam WY, Gopal R, Kang DD, Ahmed M, Rajamanickam A, Cruz-Lagunas A, Zuniga J, Babu S, Kolls JK, Mitreva M, Rosa BA, Ramos-Payan R, Morrison TE, Murray PJ, Rangel-Moreno J, Pearce EJ, Khader SA (2015) Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis. J Clin Invest 125(12):4699–4713. https://doi.org/10.1172/JCI77378

    Article  PubMed  PubMed Central  Google Scholar 

  64. Blanco JL, Garcia ME (2008) Immune response to fungal infections. Vet Immunol Immunopathol 125(1–2):47–70. https://doi.org/10.1016/j.vetimm.2008.04.020

    Article  PubMed  CAS  Google Scholar 

  65. Doherty TA, Khorram N, Chang JE, Kim HK, Rosenthal P, Croft M, Broide DH (2012) STAT6 regulates natural helper cell proliferation during lung inflammation initiated by Alternaria. American journal of physiology Lung cellular and molecular physiology 303(7):L577–L588. https://doi.org/10.1152/ajplung.00174.2012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Van Dyken SJ, Mohapatra A, Nussbaum JC, Molofsky AB, Thornton EE, Ziegler SF, McKenzie AN, Krummel MF, Liang HE, Locksley RM (2014) Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and gammadelta T cells. Immunity 40(3):414–424. https://doi.org/10.1016/j.immuni.2014.02.003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Wiesner DL, Smith KD, Kashem SW, Bohjanen PR, Nielsen K (2017) Different lymphocyte populations direct dichotomous eosinophil or neutrophil responses to pulmonary Cryptococcus infection. J Immunol 198(4):1627–1637. https://doi.org/10.4049/jimmunol.1600821

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Piehler D, Eschke M, Schulze B, Protschka M, Muller U, Grahnert A, Richter T, Heyen L, Kohler G, Brombacher F, Alber G (2016) The IL-33 receptor (ST2) regulates early IL-13 production in fungus-induced allergic airway inflammation. Mucosal Immunol 9(4):937–949. https://doi.org/10.1038/mi.2015.106

    Article  PubMed  CAS  Google Scholar 

  69. Flaczyk A, Duerr CU, Shourian M, Lafferty EI, Fritz JH, Qureshi ST (2013) IL-33 signaling regulates innate and adaptive immunity to Cryptococcus neoformans. J Immunol 191(5):2503–2513. https://doi.org/10.4049/jimmunol.1300426

    Article  PubMed  CAS  Google Scholar 

  70. Wick G, Backovic A, Rabensteiner E, Plank N, Schwentner C, Sgonc R (2010) The immunology of fibrosis: innate and adaptive responses. Trends Immunol 31(3):110–119. https://doi.org/10.1016/j.it.2009.12.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Wynn TA (2004) Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 4(8):583–594. https://doi.org/10.1038/nri1412

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Wynn TA, Ramalingam TR (2012) Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 18(7):1028–1040. https://doi.org/10.1038/nm.2807

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Meng X-M, Nikolic-Paterson DJ, Lan HY (2014) Inflammatory processes in renal fibrosis. Nat Rev Nephrol 10:493–503. https://doi.org/10.1038/nrneph.2014.114

    Article  PubMed  CAS  Google Scholar 

  74. Gieseck Iii RL, Wilson MS, Wynn TA (2017) Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol 18:62–76. https://doi.org/10.1038/nri.2017.90

    Article  CAS  Google Scholar 

  75. Meng X, Nikolic-Paterson DJ, Lan HY (2016) TGF-β: the master regulator of fibrosis. Nature Reviews Nephrology 12:325–338. https://doi.org/10.1038/nrneph.2016.48

    Article  PubMed  CAS  Google Scholar 

  76. Gause WC, Wynn TA, Allen JE (2013) Type 2 immunity and wound healing: evolutionary refinement of adaptive immunity by helminths. Nat Rev Immunol 13:607–614. https://doi.org/10.1038/nri3476

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Hammad H, Lambrecht BN (2015) Barrier epithelial cells and the control of type 2 immunity. Immunity 43 (1):29–40. doi:https://doi.org/10.1016/j.immuni.2015.07.007

  78. Bellini A, Marini MA, Bianchetti L, Barczyk M, Schmidt M, Mattoli S (2012) Interleukin (IL)-4, IL-13, and IL-17A differentially affect the profibrotic and proinflammatory functions of fibrocytes from asthmatic patients. Mucosal Immunol 5(2):140–149. https://doi.org/10.1038/mi.2011.60

    Article  PubMed  CAS  Google Scholar 

  79. Kolodsick JE, Toews GB, Jakubzick C, Hogaboam C, Moore TA, McKenzie A, Wilke CA, Chrisman CJ, Moore BB (2004) Protection from fluorescein isothiocyanate-induced fibrosis in IL-13-deficient, but not IL-4-deficient, mice results from impaired collagen synthesis by fibroblasts. J Immunol 172(7):4068–4076

    Article  PubMed  CAS  Google Scholar 

  80. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA (1999) Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 103(6):779–788. https://doi.org/10.1172/JCI5909

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. McHedlidze T, Waldner M, Zopf S, Walker J, Rankin AL, Schuchmann M, Voehringer D, McKenzie AN, Neurath MF, Pflanz S, Wirtz S (2013) Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39(2):357–371. https://doi.org/10.1016/j.immuni.2013.07.018

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA (1999) An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest 104(6):777–785. https://doi.org/10.1172/JCI7325

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN (2000) Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol 164(5):2585–2591

    Article  PubMed  CAS  Google Scholar 

  84. Bailey JR, Bland PW, Tarlton JF, Peters I, Moorghen M, Sylvester PA, Probert CS, Whiting CV (2012) IL-13 promotes collagen accumulation in Crohn’s disease fibrosis by down-regulation of fibroblast MMP synthesis: a role for innate lymphoid cells? PLoS One 7(12):e52332. https://doi.org/10.1371/journal.pone.0052332

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455. https://doi.org/10.1038/nature12034

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V, Shipley JM, Gotwals P, Noble P, Chen Q, Senior RM, Elias JA (2001) Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med 194(6):809–821

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Han Y, Chen Y, Liu X, Zhang J, Su H, Wen H, Li W, Yao X (2017) Efficacy and safety of dupilumab for the treatment of adult atopic dermatitis: a meta-analysis of randomized clinical trials. J Allergy Clin Immunol 140(3):888–891 e886. https://doi.org/10.1016/j.jaci.2017.04.015

    Article  PubMed  CAS  Google Scholar 

  88. Parker JM, Glaspole IN, Lancaster LH, Haddad TJ, She D, Roseti SL, Fiening JP, Grant EP, Kell CM, Flaherty KR (2017) A phase 2 randomized controlled study of tralokinumab in subjects with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 197:94–103. https://doi.org/10.1164/rccm.201704-0784OC

    Article  Google Scholar 

  89. Aceves SS (2014) Remodeling and fibrosis in chronic eosinophil inflammation. Dig Dis 32(1–2):15–21. https://doi.org/10.1159/000357004

    Article  PubMed  PubMed Central  Google Scholar 

  90. Monticelli LA, Osborne LC, Noti M, Tran SV, Zaiss DM, Artis D (2015) IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. Proc Natl Acad Sci U S A 112(34):10762–10767. https://doi.org/10.1073/pnas.1509070112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Zhou Y, Lee JY, Lee CM, Cho WK, Kang MJ, Koff JL, Yoon PO, Chae J, Park HO, Elias JA, Lee CG (2012) Amphiregulin, an epidermal growth factor receptor ligand, plays an essential role in the pathogenesis of transforming growth factor-beta-induced pulmonary fibrosis. J Biol Chem 287(50):41991–42000. https://doi.org/10.1074/jbc.M112.356824

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Perugorria MJ, Latasa MU, Nicou A, Cartagena-Lirola H, Castillo J, Goni S, Vespasiani-Gentilucci U, Zagami MG, Lotersztajn S, Prieto J, Berasain C, Avila MA (2008) The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis. Hepatology 48(4):1251–1261. https://doi.org/10.1002/hep.22437

    Article  PubMed  CAS  Google Scholar 

  93. 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):367–372. doi:https://doi.org/10.1073/pnas.1315854111

  94. Yao X, Wang W, Li Y, Lv Z, Guo R, Corrigan CJ, Ding G, Huang K, Sun Y, Ying S (2015) Characteristics of IL-25 and allergen-induced airway fibrosis in a murine model of asthma. Respirology 20(5):730–738. https://doi.org/10.1111/resp.12546

    Article  PubMed  Google Scholar 

  95. Li D, Guabiraba R, Besnard AG, Komai-Koma M, Jabir MS, Zhang L, Graham GJ, Kurowska-Stolarska M, Liew FY, McSharry C, Xu D (2014) IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. J Allergy Clin Immunol 134(6):1422–1432 e1411. https://doi.org/10.1016/j.jaci.2014.05.011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Drake LY, Kita H (2017) IL-33: biological properties, functions, and roles in airway disease. Immunol Rev 278(1):173–184. https://doi.org/10.1111/imr.12552

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Roussel L, Farias R, Rousseau S (2013) IL-33 is expressed in epithelia from patients with cystic fibrosis and potentiates neutrophil recruitment. J Allergy Clin Immunol 131(3):913–916. https://doi.org/10.1016/j.jaci.2012.10.019

    Article  PubMed  CAS  Google Scholar 

  98. Moretti S, Renga G, Oikonomou V, Galosi C, Pariano M, Iannitti RG, Borghi M, Puccetti M, De Zuani M, Pucillo CE, Paolicelli G, Zelante T, Renauld JC, Bereshchenko O, Sportoletti P, Lucidi V, Russo MC, Colombo C, Fiscarelli E, Lass-Florl C, Majo F, Ricciotti G, Ellemunter H, Ratclif L, Talesa VN, Napolioni V, Romani L (2017) A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis. Nat Commun 8:14017. https://doi.org/10.1038/ncomms14017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Marvie P, Lisbonne M, L'Helgoualc'h A, Rauch M, Turlin B, Preisser L, Bourd-Boittin K, Theret N, Gascan H, Piquet-Pellorce C, Samson M (2010) Interleukin-33 overexpression is associated with liver fibrosis in mice and humans. J Cell Mol Med 14(6B):1726–1739. https://doi.org/10.1111/j.1582-4934.2009.00801.x

    Article  PubMed  CAS  Google Scholar 

  100. Liu Y, Meyer C, Muller A, Herweck F, Li Q, Mullenbach R, Mertens PR, Dooley S, Weng HL (2011) IL-13 induces connective tissue growth factor in rat hepatic stellate cells via TGF-beta-independent Smad signaling. J Immunol 187(5):2814–2823. https://doi.org/10.4049/jimmunol.1003260

    Article  PubMed  CAS  Google Scholar 

  101. Forkel M, Berglin L, Kekalainen E, Carlsson A, Svedin E, Michaelsson J, Nagasawa M, Erjefalt JS, Mori M, Flodstrom-Tullberg M, Bergquist A, Ljunggren HG, Westgren M, Lindforss U, Friberg D, Jorns C, Ellis E, Bjorkstrom NK, Mjosberg J (2017) Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers. Eur J Immunol 47(8):1280–1294. https://doi.org/10.1002/eji.201646890

    Article  PubMed  CAS  Google Scholar 

  102. Jeffery HC, McDowell P, Lutz P, Wawman RE, Roberts S, Bagnall C, Birtwistle J, Adams DH, Oo YH (2017) Human intrahepatic ILC2 are IL-13positive amphiregulinpositive and their frequency correlates with model of end stage liver disease score. PLoS One 12(12):e0188649. https://doi.org/10.1371/journal.pone.0188649

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Roediger B, Kyle R, Yip KH, Sumaria N, Guy TV, Kim BS, Mitchell AJ, Tay SS, Jain R, Forbes-Blom E, Chen X, Tong PL, Bolton HA, Artis D, Paul WE, Fazekas de St Groth B, Grimbaldeston MA, Le Gros G, Weninger W (2013) Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol 14 (6):564–573. doi:https://doi.org/10.1038/ni.2584

  104. Imai Y, Yasuda K, Sakaguchi Y, Haneda T, Mizutani H, Yoshimoto T, Nakanishi K, Yamanishi K (2013) Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A 110(34):13921–13926. https://doi.org/10.1073/pnas.1307321110

    Article  PubMed  PubMed Central  Google Scholar 

  105. Rankin AL, Mumm JB, Murphy E, Turner S, Yu N, McClanahan TK, Bourne PA, Pierce RH, Kastelein R, Pflanz S (2010) IL-33 induces IL-13-dependent cutaneous fibrosis. J Immunol 184(3):1526–1535. https://doi.org/10.4049/jimmunol.0903306

    Article  PubMed  CAS  Google Scholar 

  106. Jessup HK, Brewer AW, Omori M, Rickel EA, Budelsky AL, Yoon BR, Ziegler SF, Comeau MR (2008) Intradermal administration of thymic stromal lymphopoietin induces a T cell- and eosinophil-dependent systemic Th2 inflammatory response. J Immunol 181(6):4311–4319

    Article  PubMed  CAS  Google Scholar 

  107. Wohlfahrt T, Usherenko S, Englbrecht M, Dees C, Weber S, Beyer C, Gelse K, Distler O, Schett G, Distler JH, Ramming A (2016) Type 2 innate lymphoid cell counts are increased in patients with systemic sclerosis and correlate with the extent of fibrosis. Ann Rheum Dis 75(3):623–626. https://doi.org/10.1136/annrheumdis-2015-207388

    Article  PubMed  CAS  Google Scholar 

  108. Saunders SP, Moran T, Floudas A, Wurlod F, Kaszlikowska A, Salimi M, Quinn EM, Oliphant CJ, Nunez G, McManus R, Hams E, Irvine AD, McKenzie AN, Ogg GS, Fallon PG (2016) Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity. J Allergy Clin Immunol 137(2):482–491. https://doi.org/10.1016/j.jaci.2015.06.045

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Riedel JH, Becker M, Kopp K, Duster M, Brix SR, Meyer-Schwesinger C, Kluth LA, Gnirck AC, Attar M, Krohn S, Fehse B, Stahl RAK, Panzer U, Turner JE (2017) IL-33-mediated expansion of type 2 innate lymphoid cells protects from progressive glomerulosclerosis. Journal of the American Society of Nephrology : JASN 28(7):2068–2080. https://doi.org/10.1681/ASN.2016080877

    Article  PubMed  Google Scholar 

  110. Dalmas E, Lehmann FM, Dror E, Wueest S, Thienel C, Borsigova M, Stawiski M, Traunecker E, Lucchini FC, Dapito DH, Kallert SM, Guigas B, Pattou F, Kerr-Conte J, Maechler P, Girard JP, Konrad D, Wolfrum C, Boni-Schnetzler M, Finke D, Donath MY (2017) Interleukin-33-activated islet-resident innate lymphoid cells promote insulin secretion through myeloid cell retinoic acid production. Immunity 47(5):928–942 e927. https://doi.org/10.1016/j.immuni.2017.10.015

    Article  PubMed  CAS  Google Scholar 

  111. Masterson JC, Capocelli KE, Hosford L, Biette K, McNamee EN, de Zoeten EF, Harris R, Fernando SD, Jedlicka P, Protheroe C, Lee JJ, Furuta GT (2015) Eosinophils and IL-33 perpetuate chronic inflammation and fibrosis in a pediatric population with stricturing Crohn’s ileitis. Inflamm Bowel Dis 21(10):2429–2440. https://doi.org/10.1097/MIB.0000000000000512

    Article  PubMed  PubMed Central  Google Scholar 

  112. Scharl M, Frei S, Pesch T, Kellermeier S, Arikkat J, Frei P, Fried M, Weber A, Jehle E, Ruhl A, Rogler G (2013) Interleukin-13 and transforming growth factor beta synergise in the pathogenesis of human intestinal fistulae. Gut 62(1):63–72. https://doi.org/10.1136/gutjnl-2011-300498

    Article  PubMed  CAS  Google Scholar 

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Funding

This work has received funding from the German Research Foundation (DFG) within CRC1181 (A08), the clinical research unit KFO257, the GK1660 and the SPP1656 (Intestinal microbiota). Further support was given by the Interdisciplinary Center for Clinical Research (IZKF) of the University Erlangen-Nuremberg (A75).

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  1. Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, 91052, Erlangen, Germany

    Markus Kindermann, Lisa Knipfer, Imke Atreya & Stefan Wirtz

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  1. Markus Kindermann
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  2. Lisa Knipfer
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Correspondence to Stefan Wirtz.

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This article is a contribution to the special issue on Innate Lymphoid Cells in Inflammation and Immunity - Guest Editors: Jan-Eric Turner and Georg Gasteiger

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Kindermann, M., Knipfer, L., Atreya, I. et al. ILC2s in infectious diseases and organ-specific fibrosis. Semin Immunopathol 40, 379–392 (2018). https://doi.org/10.1007/s00281-018-0677-x

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