1932

Abstract

Although, as the major organ of gas exchange, the lung is considered a nonlymphoid organ, an interconnected network of lung-resident innate cells, including epithelial cells, dendritic cells, macrophages, and natural killer cells is crucial for its protection. These cells provide defense against a daily assault by airborne bacteria, viruses, and fungi, as well as prevent the development of cancer, allergy, and the outgrowth of commensals. Our understanding of this innate immune environment has recently changed with the discovery of a family of innate lymphoid cells (ILCs): ILC1s, ILC2s, and ILC3s. All lack adaptive antigen receptors but can provide a substantial and rapid source of IFN-γ, IL-5 and IL-13, and IL-17A or IL-22, respectively. Their ability to afford immediate protection to the lung and to influence subsequent adaptive immune responses highlights the importance of understanding ILC-regulated immunity for the design of future therapeutic interventions.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-020518-114630
2019-02-10
2024-10-05
Loading full text...

Full text loading...

/deliver/fulltext/physiol/81/1/annurev-physiol-020518-114630.html?itemId=/content/journals/10.1146/annurev-physiol-020518-114630&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Kopf M, Schneider C, Nobs SP 2015. The development and function of lung-resident macrophages and dendritic cells. Nat. Immunol. 16:36–44
    [Google Scholar]
  2. 2.  Effros RM. 2006. Anatomy, development, and physiology of the lungs. GI Motil. Online (Part 1). https://doi.org/10.1038/gimo73
    [Crossref] [Google Scholar]
  3. 3. WHO (World Health Organ.). 2015. The top 10 causes of death Fact Sheet, WHO, Geneva. http://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
    [Google Scholar]
  4. 4.  Whitsett JA, Alenghat T 2015. Respiratory epithelial cells orchestrate pulmonary innate immunity. Nat. Immunol. 16:27–35
    [Google Scholar]
  5. 5.  Schneider C, Nobs SP, Heer AK, Kurrer M, Klinke G et al. 2014. Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection. PLOS Pathog 10:e1004053
    [Google Scholar]
  6. 6.  LeVine AM, Reed JA, Kurak KE, Cianciolo E, Whitsett JA 1999. GM-CSF–deficient mice are susceptible to pulmonary group B streptococcal infection. J. Clin. Investig. 103:563–69
    [Google Scholar]
  7. 7.  Gonzalez-Juarrero M, Hattle JM, Izzo A, Junqueira-Kipnis AP, Shim TS et al. 2005. Disruption of granulocyte macrophage-colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection. J. Leukoc. Biol. 77:914–22
    [Google Scholar]
  8. 8.  Kiessling R, Klein E, Pross H, Wigzell H 1975. “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur. J. Immunol. 5:117–21
    [Google Scholar]
  9. 9.  Herberman RB, Nunn ME, Holden HT, Lavrin DH 1975. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int. J. Cancer 16:230–39
    [Google Scholar]
  10. 10.  Freud AG, Yokohama A, Becknell B, Lee MT, Mao HC et al. 2006. Evidence for discrete stages of human natural killer cell differentiation in vivo. J. Exp. Med. 203:1033–43
    [Google Scholar]
  11. 11.  Mjösberg J, Spits H 2016. Human innate lymphoid cells. J. Allergy Clin. Immunol. 138:1265–76
    [Google Scholar]
  12. 12.  Colucci F, Caligiuri MA, Di Santo JP 2003. What does it take to make a natural killer?. Nat. Rev. Immunol. 3:413–25
    [Google Scholar]
  13. 13.  Gregoire C, Chasson L, Luci C, Tomasello E, Geissmann F et al. 2007. The trafficking of natural killer cells. Immunol. Rev. 220:169–82
    [Google Scholar]
  14. 14.  Marquardt N, Kekalainen E, Chen P, Kvedaraite E, Wilson JN et al. 2017. Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69CD56dim cells. J. Allergy Clin. Immunol. 139:1321–30.e4
    [Google Scholar]
  15. 15.  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. 13:145–49
    [Google Scholar]
  16. 16.  Gasteiger G, Fan X, Dikiy S, Lee SY, Rudensky AY 2015. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350:981–85
    [Google Scholar]
  17. 17.  Huang Y, Mao K, Chen X, Sun MA, Kawabe T et al. 2018. S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense. Science 359:114–19
    [Google Scholar]
  18. 18.  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. 12:1045–54
    [Google Scholar]
  19. 19.  Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR 1993. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. 178:2249–54
    [Google Scholar]
  20. 20.  Cooper AM, Magram J, Ferrante J, Orme IM 1997. Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis. J. Exp. Med 186:39–45
    [Google Scholar]
  21. 21.  Amsen D, Spilianakis CG, Flavell RA 2009. How are TH1 and TH2 effector cells made?. Curr. Opin. Immunol. 21:153–60
    [Google Scholar]
  22. 22.  Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B et al. 2003. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–48
    [Google Scholar]
  23. 23.  Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C et al. 2005. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med 202:761–69
    [Google Scholar]
  24. 24.  Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B 2006. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–89
    [Google Scholar]
  25. 25.  Stockinger B, Omenetti S 2017. The dichotomous nature of T helper 17 cells. Nat. Rev. Immunol. 17:535–44
    [Google Scholar]
  26. 26.  Walker JA, McKenzie ANJ 2018. TH2 cell development and function. Nat. Rev. Immunol. 18:121–33
    [Google Scholar]
  27. 27.  Fallon PG, Jolin HE, Smith P, Emson CL, Townsend MJ et al. 2002. IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17:7–17
    [Google Scholar]
  28. 28.  McKenzie GJ, Emson CL, Bell SE, Anderson S, Fallon P et al. 1998. Impaired development of Th2 cells in IL-13-deficient mice. Immunity 9:423–32
    [Google Scholar]
  29. 29.  Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG 1996. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med. 183:195–201
    [Google Scholar]
  30. 30.  Kearley J, Erjefalt JS, Andersson C, Benjamin E, Jones CP et al. 2011. IL-9 governs allergen-induced mast cell numbers in the lung and chronic remodeling of the airways. Am. J. Respir. Crit. Care Med. 183:865–75
    [Google Scholar]
  31. 31.  Walter DM, McIntire JJ, Berry G, McKenzie ANJ, Donaldson DD et al. 2001. Critical role for IL-13 in the development of allergen-induced airway hyperreactivity. J. Immunol. 167:4668–75
    [Google Scholar]
  32. 32.  Corry DB, Grünig G, Hadeiba H, Kurup VP, Warnock ML et al. 1998. Requirements for allergen-induced airway hyperreactivity in T and B cell–deficient mice. Mol. Med. 4:344–55
    [Google Scholar]
  33. 33.  Voehringer D, Reese TA, Huang X, Shinkai K, Locksley RM 2006. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J. Exp. Med. 203:1435–46
    [Google Scholar]
  34. 34.  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. 203:1105–16
    [Google Scholar]
  35. 35.  Fort MM, Cheung J, Yen D, Li J, Zurawski SM et al. 2001. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15:985–95
    [Google Scholar]
  36. 36.  Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T et al. 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. 169:443–53
    [Google Scholar]
  37. 37.  Schmitz J, Owyang A, Oldham E, Song Y, Murphy E et al. 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 23:479–90
    [Google Scholar]
  38. 38.  Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T et al. 2010. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463:540–44
    [Google Scholar]
  39. 39.  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 464:1367–70
    [Google Scholar]
  40. 40.  Price AE, Liang HE, Sullivan BM, Reinhardt RL, Eisley CJ et al. 2010. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. PNAS 107:11489–94
    [Google Scholar]
  41. 41.  Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH et al. 2012. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J. Allergy Clin. Immunol. 129:191–98.e4
    [Google Scholar]
  42. 42.  Klein Wolterink RGJ, Kleinjan A, van Nimwegen M, Bergen I, de Bruijn M et al. 2012. Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur. J. Immunol. 42:1106–16
    [Google Scholar]
  43. 43.  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. 129:216–27.e6
    [Google Scholar]
  44. 44.  Halim TY, Krauss RH, Sun AC, Takei F 2012. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36:451–63
    [Google Scholar]
  45. 45.  Molofsky AB, Nussbaum JC, Liang HE, Van Dyken SJ, Cheng LE et al. 2013. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210:535–49
    [Google Scholar]
  46. 46.  Nussbaum JC, Van Dyken SJ, von Moltke J, Cheng LE, Mohapatra A et al. 2013. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502:245–48
    [Google Scholar]
  47. 47.  Mjösberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM et al. 2011. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. 12:1055–62
    [Google Scholar]
  48. 48.  Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA et al. 2013. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci. Transl. Med. 5:170ra16
    [Google Scholar]
  49. 49.  Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D et al. 2013. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J. Exp. Med. 210:2939–50
    [Google Scholar]
  50. 50.  Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR et al. 2010. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464:1371–75
    [Google Scholar]
  51. 51.  Satoh-Takayama N, Vosshenrich CAJ, Lesjean-Pottier S, Sawa S, Lochner M et al. 2008. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29:958–70
    [Google Scholar]
  52. 52.  Sanos SL, Bui VL, Mortha A, Oberle K, Heners C et al. 2009. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol. 10:83–91
    [Google Scholar]
  53. 53.  Luci C, Reynders A, Ivanov II, Cognet C, Chiche L et al. 2009. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10:75–82
    [Google Scholar]
  54. 54.  Daussy C, Faure F, Mayol K, Viel S, Gasteiger G et al. 2014. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J. Exp. Med. 211:563–77
    [Google Scholar]
  55. 55.  Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S et al. 2012. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36:55–67
    [Google Scholar]
  56. 56.  Klose CSN, Flach M, Möhle L, Rogell L, Hoyler T et al. 2014. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157:340–56
    [Google Scholar]
  57. 57.  Yagi R, Zhong C, Northrup DL, Yu F, Bouladoux N et al. 2014. The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity 40:378–88
    [Google Scholar]
  58. 58.  Pikovskaya O, Chaix J, Rothman NJ, Collins A, Chen YH et al. 2016. Cutting edge: eomesodermin is sufficient to direct type 1 innate lymphocyte development into the conventional NK lineage. J. Immunol. 196:1449–54
    [Google Scholar]
  59. 59.  Kim S, Iizuka K, Kang HS, Dokun A, French AR et al. 2002. In vivo developmental stages in murine natural killer cell maturation. Nat. Immunol. 3:523–28
    [Google Scholar]
  60. 60.  Chiossone L, Chaix J, Fuseri N, Roth C, Vivier E, Walzer T 2009. Maturation of mouse NK cells is a 4-stage developmental program. Blood 113:5488–96
    [Google Scholar]
  61. 61.  Hayakawa Y, Smyth MJ 2006. CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J. Immunol. 176:1517–24
    [Google Scholar]
  62. 62.  Mayol K, Biajoux V, Marvel J, Balabanian K, Walzer T 2011. Sequential desensitization of CXCR4 and S1P5 controls natural killer cell trafficking. Blood 118:4863–71
    [Google Scholar]
  63. 63.  Despoix N, Walzer T, Jouve N, Blot-Chabaud M, Bardin N et al. 2008. Mouse CD146/MCAM is a marker of natural killer cell maturation. Eur. J. Immunol. 38:2855–64
    [Google Scholar]
  64. 64.  Huntington ND, Tabarias H, Fairfax K, Brady J, Hayakawa Y et al. 2007. NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J. Immunol. 178:4764–70
    [Google Scholar]
  65. 65.  Zhang J, Marotel M, Fauteux-Daniel S, Mathieu AL, Viel S et al. 2018. T-bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1. Eur. J. Immunol. 48:738–50
    [Google Scholar]
  66. 66.  Townsend MJ, Weinmann AS, Matsuda JL, Salomon R, Farnham PJ et al. 2004. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells. Immunity 20:477–94
    [Google Scholar]
  67. 67.  Jenne CN, Enders A, Rivera R, Watson SR, Bankovich AJ et al. 2009. T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. J. Exp. Med. 206:2469–81
    [Google Scholar]
  68. 68.  Robbins SH, Tessmer MS, Van Kaer L, Brossay L 2005. Direct effects of T-bet and MHC class I expression, but not STAT1, on peripheral NK cell maturation. Eur. J. Immunol. 35:757–65
    [Google Scholar]
  69. 69.  Takeda K, Cretney E, Hayakawa Y, Ota T, Akiba H et al. 2005. TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. Blood 105:2082–89
    [Google Scholar]
  70. 70.  Lim AI, Menegatti S, Bustamante J, Le Bourhis L, Allez M et al. 2016. IL-12 drives functional plasticity of human group 2 innate lymphoid cells. J. Exp. Med. 213:569–83
    [Google Scholar]
  71. 71.  Ohne Y, Silver JS, Thompson-Snipes L, Collet MA, Blanck JP et al. 2016. IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat. Immunol. 17:646–55
    [Google Scholar]
  72. 72.  Klose CS, Kiss EA, Schwierzeck V, Ebert K, Hoyler T et al. 2013. A T-bet gradient controls the fate and function of CCR6RORγt+ innate lymphoid cells. Nature 494:261–65
    [Google Scholar]
  73. 73.  Bernink JH, Krabbendam L, Germar K, de Jong E, Gronke K et al. 2015. Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43:146–60
    [Google Scholar]
  74. 74.  Bal SM, Bernink JH, Nagasawa M, Groot J, Shikhagaie MM et al. 2016. IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat. Immunol. 17:636–45
    [Google Scholar]
  75. 75.  Simoni Y, Fehlings M, Kloverpris HN, McGovern N, Koo SL et al. 2017. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity 46:148–61
    [Google Scholar]
  76. 76.  Björklund AK, Forkel M, Picelli S, Konya V, Theorell J et al. 2016. The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing. Nat. Immunol. 17:451–60
    [Google Scholar]
  77. 77.  Silver JS, Kearley J, Copenhaver AM, Sanden C, Mori M et al. 2016. Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. Nat. Immunol. 17:626–35
    [Google Scholar]
  78. 78.  Ghadially H, Horani A, Glasner A, Elboim M, Gazit R et al. 2013. NKp46 regulates allergic responses. Eur. J. Immunol. 43:3006–16
    [Google Scholar]
  79. 79.  Farhadi N, Lambert L, Triulzi C, Openshaw PJ, Guerra N, Culley FJ 2014. Natural killer cell NKG2D and granzyme B are critical for allergic pulmonary inflammation. J. Allergy Clin. Immunol. 133:827–35.e3
    [Google Scholar]
  80. 80.  Haspeslagh E, van Helden MJ, Deswarte K, De Prijck S, van Moorleghem J et al. 2018. Role of NKp46+ natural killer cells in house dust mite-driven asthma. EMBO Mol. Med. 10:e8657
    [Google Scholar]
  81. 81.  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 37:634–48
    [Google Scholar]
  82. 82.  Liang HE, Reinhardt RL, Bando JK, Sullivan BM, Ho IC, Locksley RM 2011. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 13:58–66
    [Google Scholar]
  83. 83.  Mjösberg J, Bernink J, Golebski K, Karrich JJ, Peters CP et al. 2012. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37:649–59
    [Google Scholar]
  84. 84.  Wong SH, Walker JA, Jolin HE, Drynan LF, Hams E et al. 2012. Transcription factor RORα is critical for nuocyte development. Nat. Immunol. 13:229–36
    [Google Scholar]
  85. 85.  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 37:463–74
    [Google Scholar]
  86. 86.  Spooner CJ, Lesch J, Yan D, Khan AA, Abbas A et al. 2013. Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1. Nat. Immunol. 14:1229–36
    [Google Scholar]
  87. 87.  Walker JA, Oliphant CJ, Englezakis A, Yu Y, Clare S et al. 2015. Bcl11b is essential for group 2 innate lymphoid cell development. J. Exp. Med. 212:875–82
    [Google Scholar]
  88. 88.  Yu Y, Wang C, Clare S, Wang J, Lee SC et al. 2015. The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development. J. Exp. Med. 212:865–74
    [Google Scholar]
  89. 89.  Califano D, Cho JJ, Uddin MN, Lorentsen KJ, Yang Q et al. 2015. Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity 43:354–68
    [Google Scholar]
  90. 90.  Yang Q, Monticelli LA, Saenz SA, Chi AW, Sonnenberg GF et al. 2013. T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity 38:694–704
    [Google Scholar]
  91. 91.  Mielke LA, Groom JR, Rankin LC, Seillet C, Masson F et al. 2013. TCF-1 controls ILC2 and NKp46+RORγt+ innate lymphocyte differentiation and protection in intestinal inflammation. J. Immunol. 191:4383–91
    [Google Scholar]
  92. 92.  Johansson K, Malmhall C, Ramos-Ramirez P, Radinger M 2017. MicroRNA-155 is a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation. J. Allergy Clin. Immunol. 139:1007–16.e9
    [Google Scholar]
  93. 93.  Huang Y, Guo L, Qiu J, Chen X, Hu-Li J et al. 2015. IL-25-responsive, lineage-negative KLRG1hi cells are multipotential ‘inflammatory’ type 2 innate lymphoid cells. Nat. Immunol. 16:161–69
    [Google Scholar]
  94. 94.  Duerr CU, McCarthy CD, Mindt BC, Rubio M, Meli AP et al. 2016. Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells. Nat. Immunol. 17:65–75
    [Google Scholar]
  95. 95.  Moro K, Kabata H, Tanabe M, Koga S, Takeno N et al. 2016. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. Nat. Immunol. 17:76–86
    [Google Scholar]
  96. 96.  De Grove KC, Provoost S, Verhamme FM, Bracke KR, Joos GF et al. 2016. Characterization and quantification of innate lymphoid cell subsets in human lung. PLOS ONE 11:e0145961
    [Google Scholar]
  97. 97.  Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E et al. 2010. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363:1211–21
    [Google Scholar]
  98. 98.  Bønnelykke K, Sleiman P, Nielsen K, Kreiner-Møller E, Mercader JM et al. 2014. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat. Genet. 46:51–55
    [Google Scholar]
  99. 99.  Bartemes KR, Kephart GM, Fox SJ, Kita H 2014. Enhanced innate type 2 immune response in peripheral blood from patients with asthma. J. Allergy Clin. Immunol. 134:671–78.e4
    [Google Scholar]
  100. 100.  Jia Y, Fang X, Zhu X, Bai C, Zhu L et al. 2016. IL-13+ type 2 innate lymphoid cells correlate with asthma control status and treatment response. Am. J. Respir. Cell Mol. Biol. 55:675–83
    [Google Scholar]
  101. 101.  Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria JP et al. 2016. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J. Allergy Clin. Immunol. 137:75–86.e8
    [Google Scholar]
  102. 102.  Nagakumar P, Denney L, Fleming L, Bush A, Lloyd CM, Saglani S 2016. Type 2 innate lymphoid cells in induced sputum from children with severe asthma. J. Allergy Clin. Immunol. 137:624–26.e6
    [Google Scholar]
  103. 103.  Liu S, Verma M, Michalec L, Liu W, Sripada A et al. 2018. Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: the role of thymic stromal lymphopoietin. J. Allergy Clin. Immunol. 141:257–68.e6
    [Google Scholar]
  104. 104.  Kabata H, Moro K, Fukunaga K, Suzuki Y, Miyata J et al. 2013. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat. Commun. 4:2675
    [Google Scholar]
  105. 105.  Cheng D, Xue Z, Yi L, Shi H, Zhang K et al. 2014. Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma. Am. J. Respir. Crit. Care Med. 190:639–48
    [Google Scholar]
  106. 106.  Li Y, Wang W, Lv Z, Li Y, Chen Y et al. 2018. Elevated expression of IL-33 and TSLP in the airways of human asthmatics in vivo: a potential biomarker of severe refractory disease. J. Immunol. 200:2253–62
    [Google Scholar]
  107. 107.  Oboki K, Ohno T, Kajiwara N, Arae K, Morita H et al. 2010. IL-33 is a crucial amplifier of innate rather than acquired immunity. PNAS 107:18581–86
    [Google Scholar]
  108. 108.  Barlow JL, Peel S, Fox J, Panova V, Hardman CS et al. 2013. IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction. J. Allergy Clin. Immunol. 132:933–41
    [Google Scholar]
  109. 109.  Van Dyken SJ, Mohapatra A, Nussbaum JC, Molofsky AB, Thornton EE et al. 2014. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and δγ T cells. Immunity 40:414–24
    [Google Scholar]
  110. 110.  Hardman CS, Panova V, McKenzie ANJ 2013. IL-33 citrine reporter mice reveal the temporal and spatial expression of IL-33 during allergic lung inflammation. Eur. J. Immunol. 43:488–98
    [Google Scholar]
  111. 111.  Saglani S, Lui S, Ullmann N, Campbell GA, Sherburn RT et al. 2013. IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma. J. Allergy Clin. Immunol. 132:676–85.e13
    [Google Scholar]
  112. 112.  de Kleer IM, Kool M, de Bruijn MJ, Willart M, van Moorleghem J et al. 2016. Perinatal activation of the interleukin-33 pathway promotes type 2 immunity in the developing lung. Immunity 45:1285–98
    [Google Scholar]
  113. 113.  Saluzzo S, Gorki AD, Rana BMJ, Martins R, Scanlon S et al. 2017. First-breath-induced type 2 pathways shape the lung immune environment. Cell Rep 18:1893–905
    [Google Scholar]
  114. 114.  Motomura Y, Morita H, Moro K, Nakae S, Artis D et al. 2014. Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation. Immunity 40:758–71
    [Google Scholar]
  115. 115.  Denney L, Byrne AJ, Shea TJ, Buckley JS, Pease JE et al. 2015. Pulmonary epithelial cell-derived cytokine TGF-β1 is a critical cofactor for enhanced innate lymphoid cell function. Immunity 43:945–58
    [Google Scholar]
  116. 116.  Wilhelm C, Hirota K, Stieglitz B, Van Snick J, Tolaini M et al. 2011. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12:1071–77
    [Google Scholar]
  117. 117.  Mohapatra A, Van Dyken SJ, Schneider C, Nussbaum JC, Liang HE, Locksley RM 2016. Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis. Mucosal Immunol 9:275–86
    [Google Scholar]
  118. 118.  Turner JE, Morrison PJ, Wilhelm C, Wilson M, Ahlfors H et al. 2013. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J. Exp. Med. 210:2951–65
    [Google Scholar]
  119. 119.  Xue L, Salimi M, Panse I, Mjösberg JM, McKenzie ANJ et al. 2014. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J. Allergy Clin. Immunol. 133:1184–94.e7
    [Google Scholar]
  120. 120.  Barnig C, Cernadas M, Dutile S, Liu X, Perrella MA et al. 2013. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci. Transl. Med. 5:174ra26
    [Google Scholar]
  121. 121.  Oliphant CJ, Hwang YY, Walker JA, Salimi M, Wong SH et al. 2014. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41:283–95
    [Google Scholar]
  122. 122.  Mirchandani AS, Besnard AG, Yip E, Scott C, Bain CC et al. 2014. Type 2 innate lymphoid cells drive CD4+ Th2 cell responses. J. Immunol. 192:2442–48
    [Google Scholar]
  123. 123.  Halim TY, Steer CA, Matha L, Gold MJ, Martinez-Gonzalez I et al. 2014. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40:425–35
    [Google Scholar]
  124. 124.  Schwartz C, Khan AR, Floudas A, Saunders SP, Hams E et al. 2017. ILC2s regulate adaptive Th2 cell functions via PD-L1 checkpoint control. J. Exp. Med. 214:2507–21
    [Google Scholar]
  125. 125.  Maazi H, Patel N, Sankaranarayanan I, Suzuki Y, Rigas D et al. 2015. ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity. Immunity 42:538–51
    [Google Scholar]
  126. 126.  Kamachi F, Isshiki T, Harada N, Akiba H, Miyake S 2015. ICOS promotes group 2 innate lymphoid cell activation in lungs. Biochem. Biophys. Res. Commun. 463:739–45
    [Google Scholar]
  127. 127.  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. 45:2766–72
    [Google Scholar]
  128. 128.  Yu Y, Tsang JC, Wang C, Clare S, Wang J et al. 2016. Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its development pathway. Nature 539:102–6
    [Google Scholar]
  129. 129.  Taylor S, Huang Y, Mallett G, Stathopoulou C, Felizardo TC et al. 2017. PD-1 regulates KLRG1+ group 2 innate lymphoid cells. J. Exp. Med. 214:1663–78
    [Google Scholar]
  130. 130.  Nagashima H, Okuyama Y, Fujita T, Takeda T, Motomura Y et al. 2018. GITR cosignal in ILC2s controls allergic lung inflammation. J. Allergy Clin. Immunol. 141:1939–43.e8
    [Google Scholar]
  131. 131.  Mebius RE, Streeter PR, Michie S, Butcher EC, Weissman IL 1996. A developmental switch in lymphocyte homing receptor and endothelial vascular addressin expression regulates lymphocyte homing and permits CD4+ CD3 cells to colonize lymph nodes. PNAS 93:11019–24
    [Google Scholar]
  132. 132.  Mebius RE, Rennert P, Weissman IL 1997. Developing lymph nodes collect CD4+CD3 LTβ+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7:493–504
    [Google Scholar]
  133. 133.  Yoshida H, Honda K, Shinkura R, Adachi S, Nishikawa S et al. 1999. IL-7 receptor α+ CD3 cells in the embryonic intestine induces the organizing center of Peyer's patches. Int. Immunol. 11:643–55
    [Google Scholar]
  134. 134.  Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR 2004. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5:64–73
    [Google Scholar]
  135. 135.  Sun Z, Unutmaz D, Zou YR, Sunshine MJ, Pierani A et al. 2000. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288:2369–73
    [Google Scholar]
  136. 136.  De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A et al. 1994. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264:703–7
    [Google Scholar]
  137. 137.  Gronke K, Kofoed-Nielsen M, Diefenbach A 2016. Innate lymphoid cells, precursors and plasticity. Immunol. Lett. 179:9–18
    [Google Scholar]
  138. 138.  Cherrier M, Sawa S, Eberl G 2012. Notch, Id2, and RORγt sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J. Exp. Med. 209:729–40
    [Google Scholar]
  139. 139.  Yokota Y, Mansouri A, Mori S, Sugawara S, Adachi S et al. 1999. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397:702–6
    [Google Scholar]
  140. 140.  Vonarbourg C, Mortha A, Bui VL, Hernandez PP, Kiss EA et al. 2010. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33:736–51
    [Google Scholar]
  141. 141.  Sawa S, Lochner M, Satoh-Takayama N, Dulauroy S, Bérard M et al. 2011. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12:320–26
    [Google Scholar]
  142. 142.  Withers DR, Hepworth MR, Wang X, Mackley EC, Halford EE et al. 2016. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat. Med. 22:319–23
    [Google Scholar]
  143. 143.  Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D et al. 2011. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334:1561–65
    [Google Scholar]
  144. 144.  Moffatt MF, Cookson WO 2017. The lung microbiome in health and disease. Clin. Med. 17:525–29
    [Google Scholar]
  145. 145.  Hilty M, Burke C, Pedro H, Cardenas P, Bush A et al. 2010. Disordered microbial communities in asthmatic airways. PLOS ONE 5:e8578
    [Google Scholar]
  146. 146.  Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM et al. 2004. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N. Engl. J. Med. 350:2645–53
    [Google Scholar]
  147. 147.  Yadava K, Bollyky P, Lawson MA 2016. The formation and function of tertiary lymphoid follicles in chronic pulmonary inflammation. Immunology 149:262–69
    [Google Scholar]
  148. 148.  van de Pavert SA, Olivier BJ, Goverse G, Vondenhoff MF, Greuter M et al. 2009. Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat. Immunol. 10:1193–99
    [Google Scholar]
  149. 149.  Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M, Hwang JY, Kusser K et al. 2011. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol. 12:639–46
    [Google Scholar]
  150. 150.  Van Maele L, Carnoy C, Cayet D, Ivanov S, Porte R et al. 2014. Activation of type 3 innate lymphoid cells and interleukin 22 secretion in the lungs during Streptococcus pneumoniae infection. J. Infect. Dis. 210:493–503
    [Google Scholar]
  151. 151.  Carrega P, Loiacono F, Di Carlo E, Scaramuccia A, Mora M et al. 2015. NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures. Nat. Commun. 6:8280
    [Google Scholar]
  152. 152.  Gladiator A, Wangler N, Trautwein-Weidner K, LeibundGut-Landmann S 2013. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J. Immunol. 190:521–25
    [Google Scholar]
  153. 153.  Xiong H, Keith JW, Samilo DW, Carter RA, Leiner IM, Pamer EG 2016. Innate lymphocyte/Ly6Chi monocyte crosstalk promotes Klebsiella pneumoniae clearance. Cell 165:679–89
    [Google Scholar]
  154. 154.  Taube C, Tertilt C, Gyulveszi G, Dehzad N, Kreymborg K et al. 2011. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease. PLOS ONE 6:e21799
    [Google Scholar]
  155. 155.  Kim HY, Lee HJ, Chang YJ, Pichavant M, Shore SA et al. 2014. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat. Med. 20:54–61
    [Google Scholar]
  156. 156.  Schnyder-Candrian S, Togbe D, Couillin I, Mercier I, Brombacher F et al. 2006. Interleukin-17 is a negative regulator of established allergic asthma. J. Exp. Med. 203:2715–25
    [Google Scholar]
  157. 157.  Barlow JL, Flynn RJ, Ballantyne SJ, McKenzie ANJ 2011. Reciprocal expression of IL-25 and IL-17A is important for allergic airways hyperreactivity. Clin. Exp. Allergy 41:1447–55
    [Google Scholar]
  158. 158.  Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M et al. 2008. Cluster analysis and clinical asthma phenotypes. Am. J. Respir. Crit. Care Med. 178:218–24
    [Google Scholar]
  159. 159.  Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M et al. 2007. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am. J. Respir. Crit. Care Med. 176:1062–71
    [Google Scholar]
  160. 160.  Nair P, Pizzichini MMM, Kjarsgaard M, Inman MD, Efthimiadis A et al. 2009. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N. Engl. J. Med. 360:985–93
    [Google Scholar]
  161. 161.  Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV et al. 2011. Lebrikizumab treatment in adults with asthma. N. Engl. J. Med. 365:1088–98
    [Google Scholar]
  162. 162.  Hanania NA, Korenblat P, Chapman KR, Bateman ED, Kopecky P et al. 2016. Efficacy and safety of lebrikizumab in patients with uncontrolled asthma (LAVOLTA I and LAVOLTA II): replicate, phase 3, randomised, double-blind, placebo-controlled trials. Lancet Respir. Med. 4:781–96
    [Google Scholar]
  163. 163.  Korenblat P, Kerwin E, Leshchenko I, Yen K, Holweg CTJ et al. 2018. Efficacy and safety of lebrikizumab in adult patients with mild-to-moderate asthma not receiving inhaled corticosteroids. Respir. Med. 134:143–49
    [Google Scholar]
  164. 164.  Wenzel S, Castro M, Corren J, Maspero J, Wang L et al. 2016. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 388:31–44
    [Google Scholar]
  165. 165.  Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A et al. 2016. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N. Engl. J. Med. 375:2335–48
    [Google Scholar]
  166. 166.  Beale J, Jayaraman A, Jackson DJ, Macintyre JDR, Edwards MR et al. 2014. Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation. Sci. Transl. Med. 6:256ra134
    [Google Scholar]
  167. 167.  Camelo A, Barlow JL, Drynan LF, Neill DR, Ballantyne SJ et al. 2012. Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13. J. Gastroenterol. 47:1198–211
    [Google Scholar]
  168. 168.  Gauvreau GM, O'Byrne PM, Boulet LP, Wang Y, Cockcroft D et al. 2014. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N. Engl. J. Med. 370:2102–10
    [Google Scholar]
  169. 169.  Corren J, Parnes JR, Wang L, Mo M, Roseti SL et al. 2017. Tezepelumab in adults with uncontrolled asthma. N. Engl. J. Med. 377:936–46
    [Google Scholar]
  170. 170.  Bateman ED, Guerreros AG, Brockhaus F, Holzhauer B, Pethe A et al. 2017. Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids. Eur. Respir. J. 50:1700670
    [Google Scholar]
/content/journals/10.1146/annurev-physiol-020518-114630
Loading
/content/journals/10.1146/annurev-physiol-020518-114630
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error