Respiratory virus infections, such as influenza, typically induce a robust type I (pro-inflammatory cytokine) immune response, however, the production of type 2 cytokines has been observed. Type 2 cytokine production during respiratory virus infection is linked to asthma exacerbation; however, type 2 cytokines may also be tissue protective. Interleukin (IL)-5 is a prototypical type 2 cytokine that is essential for eosinophil maturation and egress out of the bone marrow. However, little is known about the cellular source and underlying cellular and molecular basis for the regulation of IL-5 production during respiratory virus infection. Using a mouse model of influenza virus infection, we found a robust transient release of IL-5 into infected airways along with a significant and progressive accumulation of eosinophils into the lungs, particularly during the recovery phase of infection, i.e. following virus clearance. The cellular source of the IL-5 was group 2 innate lymphoid cells (ILC2) infiltrating the infected lungs. Interestingly, the progressive accumulation of eosinophils following virus clearance is reflected in the rapid expansion of c-kit+ IL-5 producing ILC2. We further demonstrate that the enhanced capacity for IL-5 production by ILC2 during recovery is concomitant with the enhanced expression of the IL-33 receptor subunit, ST2, by ILC2. Lastly, we show that NKT cells, as well as alveolar macrophages (AM), are endogenous sources of IL-33 that enhance IL-5 production from ILC2. Collectively, these results reveal that c-kit+ ILC2 interaction with IL-33 producing NKT and AM leads to abundant production of IL-5 by ILC2 and accounts for the accumulation of eosinophils observed during the recovery phase of influenza infection.
References
[1]
Oliphant CJ, Barlow JL, McKenzie AN (2011) Insights into the initiation of type 2 immune responses. Immunology 134: 378–385. doi: 10.1111/j.1365-2567.2011.03499.x
[2]
Takatsu K (2011) Interleukin-5 and IL-5 receptor in health and diseases. Proc Jpn Acad Ser B Phys Biol Sci 87: 463–485. doi: 10.2183/pjab.87.463
[3]
Lee JJ, Dimina D, Macias MP, Ochkur SI, McGarry MP, et al. (2004) Defining a link with asthma in mice congenitally deficient in eosinophils. Science 305: 1773–1776. doi: 10.1126/science.1099472
[4]
Walsh ER, Sahu N, Kearley J, Benjamin E, Kang BH, et al. (2008) Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma. J Exp Med 205: 1285–1292. doi: 10.1084/jem.20071836
[5]
Bendelja K, Gagro A, Bace A, Lokar-Kolbas R, Krsulovic-Hresic V, et al. (2000) Predominant type-2 response in infants with respiratory syncytial virus (RSV) infection demonstrated by cytokine flow cytometry. Clin Exp Immunol 121: 332–338. doi: 10.1046/j.1365-2249.2000.01297.x
[6]
Hamada H, Bassity E, Flies A, Strutt TM, Garcia-Hernandez Mde L, et al. (2013) Multiple Redundant Effector Mechanisms of CD8+ T Cells Protect against Influenza Infection. J Immunol 190: 296–306. doi: 10.4049/jimmunol.1200571
[7]
Allen JE, Wynn TA (2011) Evolution of Th2 immunity: a rapid repair response to tissue destructive pathogens. PLoS Pathog 7: e1002003. doi: 10.1371/journal.ppat.1002003
[8]
Pulendran B, Artis D (2012) New paradigms in type 2 immunity. Science 337: 431–435. doi: 10.1126/science.1221064
[9]
Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, et al. (2013) Innate lymphoid cells–a proposal for uniform nomenclature. Nat Rev Immunol 13: 145–149. doi: 10.1038/nri3365
[10]
Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, et al. (2010) Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature 463: 540–544. doi: 10.1038/nature08636
[11]
Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, et al. (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464: 1367–1370. doi: 10.1038/nature08900
[12]
Price AE, Liang HE, Sullivan BM, Reinhardt RL, Eisley CJ, et al. (2010) Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A 107: 11489–11494. doi: 10.1073/pnas.1003988107
[13]
Chang YJ, Kim HY, Albacker LA, Baumgarth N, McKenzie AN, et al. (2011) Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol 12: 631–638. doi: 10.1038/ni.2045
[14]
Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, et al. (2011) Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol 12: 1045–1054. doi: 10.1038/ni.2131
[15]
Baumgarth N, Brown L, Jackson D, Kelso A (1994) Novel features of the respiratory tract T-cell response to influenza virus infection: lung T cells increase expression of gamma interferon mRNA in vivo and maintain high levels of mRNA expression for interleukin-5 (IL-5) and IL-10. J Virol 68: 7575–7581.
[16]
Buchweitz JP, Harkema JR, Kaminski NE (2007) Time-dependent airway epithelial and inflammatory cell responses induced by influenza virus A/PR/8/34 in C57BL/6 mice. Toxicol Pathol 35: 424–435. doi: 10.1080/01926230701302558
[17]
Sarawar SR, Carding SR, Allan W, McMickle A, Fujihashi K, et al. (1993) Cytokine profiles of bronchoalveolar lavage cells from mice with influenza pneumonia: consequences of CD4+ and CD8+ T cell depletion. Reg Immunol 5: 142–150.
[18]
Hufford MM, Kim TS, Sun J, Braciale TJ (2011) Antiviral CD8+ T cell effector activities in situ are regulated by target cell type. J Exp Med 208: 167–180. doi: 10.1084/jem.20101850
[19]
Sanderson CJ (1992) Interleukin-5, eosinophils, and disease. Blood 79: 3101–3109.
[20]
Sun J, Madan R, Karp CL, Braciale TJ (2009) Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med 15: 277–284. doi: 10.1038/nm.1929
[21]
Spits H, Cupedo T (2012) Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol 30: 647–675. doi: 10.1146/annurev-immunol-020711-075053
[22]
Masson K, Ronnstrand L (2009) Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3. Cell Signal 21: 1717–1726. doi: 10.1016/j.cellsig.2009.06.002
[23]
Jamieson AM, Pasman L, Yu S, Gamradt P, Homer RJ, et al. (2013) Role of Tissue Protection in Lethal Respiratory Viral-Bacterial Coinfection. Science 340: 1230–1234. doi: 10.1126/science.1233632
[24]
Hoyler T, Klose CS, Souabni A, Turqueti-Neves A, Pfeifer D, et al. (2012) The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37: 634–648. doi: 10.1016/j.immuni.2012.06.020
[25]
Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, et al. (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: 1105–1116. doi: 10.1084/jem.20051615
[26]
Le Goffic R, Arshad MI, Rauch M, L'Helgoualc'h A, Delmas B, et al. (2011) Infection with influenza virus induces IL-33 in murine lungs. Am J Respir Cell Mol Biol 45: 1125–1132. doi: 10.1165/rcmb.2010-0516oc
[27]
Mirchandani AS, Salmond RJ, Liew FY (2012) Interleukin-33 and the function of innate lymphoid cells. Trends Immunol 33: 389–396. doi: 10.1016/j.it.2012.04.005
[28]
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: 9021–9026. doi: 10.1073/pnas.0812690106
[29]
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: e3331. doi: 10.1371/journal.pone.0003331
[30]
Talabot-Ayer D, Lamacchia C, Gabay C, Palmer G (2009) Interleukin-33 is biologically active independently of caspase-1 cleavage. J Biol Chem 284: 19420–19426. doi: 10.1074/jbc.m901744200
[31]
Bourgeois EA, Levescot A, Diem S, Chauvineau A, Berges H, et al. (2011) A natural protective function of invariant NKT cells in a mouse model of innate-cell-driven lung inflammation. Eur J Immunol 41: 299–305. doi: 10.1002/eji.201040647
[32]
Smithgall MD, Comeau MR, Yoon BR, Kaufman D, Armitage R, et al. (2008) IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int Immunol 20: 1019–1030. doi: 10.1093/intimm/dxn060
[33]
Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, et al. (1997) CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278: 1626–1629. doi: 10.1126/science.278.5343.1626
[34]
Kim HY, Chang YJ, Subramanian S, Lee HH, Albacker LA, et al. (2012) Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity. J Allergy Clin Immunol 129: 216–227 e211–216. doi: 10.1016/j.jaci.2011.10.036
[35]
Yang Q, Saenz SA, Zlotoff DA, Artis D, Bhandoola A (2011) Cutting edge: Natural helper cells derive from lymphoid progenitors. J Immunol 187: 5505–5509. doi: 10.4049/jimmunol.1102039
[36]
Wareing MD, Lyon AB, Lu B, Gerard C, Sarawar SR (2004) Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice. J Leukoc Biol 76: 886–895. doi: 10.1189/jlb.1203644
[37]
Terai M, Honda T, Yamamoto S, Yoshida M, Tsuchiya N, et al. (2011) Early induction of interleukin-5 and peripheral eosinophilia in acute pneumonia in Japanese children infected by pandemic 2009 influenza A in the Tokyo area. Microbiol Immunol 55: 341–346. doi: 10.1111/j.1348-0421.2011.00320.x
[38]
Rothenberg ME, Hogan SP (2006) The eosinophil. Annu Rev Immunol 24: 147–174. doi: 10.1146/annurev.immunol.24.021605.090720
[39]
Al-Garawi AA, Fattouh R, Walker TD, Jamula EB, Botelho F, et al. (2009) Acute, but not resolved, influenza A infection enhances susceptibility to house dust mite-induced allergic disease. J Immunol 182: 3095–3104. doi: 10.4049/jimmunol.0802837
[40]
Marsland BJ, Scanga CB, Kopf M, Le Gros G (2004) Allergic airway inflammation is exacerbated during acute influenza infection and correlates with increased allergen presentation and recruitment of allergen-specific T-helper type 2 cells. Clin Exp Allergy 34: 1299–1306. doi: 10.1111/j.1365-2222.2004.02021.x
[41]
Domachowske JB, Dyer KD, Bonville CA, Rosenberg HF (1998) Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus. J Infect Dis 177: 1458–1464. doi: 10.1086/515322
[42]
Phipps S, Lam CE, Mahalingam S, Newhouse M, Ramirez R, et al. (2007) Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus. Blood 110: 1578–1586. doi: 10.1182/blood-2007-01-071340
[43]
Chen F, Liu Z, Wu W, Rozo C, Bowdridge S, et al. (2012) An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nat Med 18: 260–266. doi: 10.1038/nm.2628
[44]
Linch SN, Danielson ET, Kelly AM, Tamakawa RA, Lee JJ, et al. (2012) Interleukin 5 is protective during sepsis in an eosinophil-independent manner. Am J Respir Crit Care Med 186: 246–254. doi: 10.1164/rccm.201201-0134oc
[45]
Lawrence CW, Braciale TJ (2004) Activation, differentiation, and migration of naive virus-specific CD8+ T cells during pulmonary influenza virus infection. J Immunol 173: 1209–1218. doi: 10.4049/jimmunol.173.2.1209
[46]
Bamias G, Martin C, Mishina M, Ross WG, Rivera-Nieves J, et al. (2005) Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation. Gastroenterology 128: 654–666. doi: 10.1053/j.gastro.2004.11.053
[47]
Pastorelli L, Garg RR, Hoang SB, Spina L, Mattioli B, et al. (2010) Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc Natl Acad Sci U S A 107: 8017–8022. doi: 10.1073/pnas.0912678107
[48]
Siegl S, Uhlig S (2012) Using the one-lung method to link p38 to pro-inflammatory gene expression during overventilation in C57BL/6 and BALB/c mice. PLoS One 7: e41464. doi: 10.1371/journal.pone.0041464
