The initiation of type 2 immune responses by the epithelial cell–derived cytokines IL-25, IL-33 and TSLP has been an area of extensive research in the past decade. Such studies have led to the identification of a new innate lymphoid subset that produces the canonical type 2 cytokines IL-5, IL-9 and IL-13 in response to IL-25 and IL-33. These group 2 or type 2 innate lymphoid cells (ILC2 cells) represent a critical source of type 2 cytokines in vivo and serve an important role in orchestrating the type 2 response to helminths and allergens. Further characterization of ILC2 cell biology will enhance the understanding of type 2 responses and may identify new treatments for asthma, allergies and parasitic infections. Interactions between ILC2 cells and the adaptive immune system, as well as examination of potential roles for ILC2 cells in the maintenance of homeostasis, promise to be particularly fruitful areas of future research.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).
Palm, N.W., Rosenstein, R.K. & Medzhitov, R. Allergic host defences. Nature 484, 465–472 (2012).
Paul, W.E. & Zhu, J. How are TH2-type immune responses initiated and amplified? Nat. Rev. Immunol. 10, 225–235 (2010).
Pulendran, B. & Artis, D. New paradigms in type 2 immunity. Science 337, 431–435 (2012).
Zhu, J., Yamane, H. & Paul, W.E. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445–489 (2010).
Zhou, B. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat. Immunol. 6, 1047–1053 (2005).
Yoo, J. et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J. Exp. Med. 202, 541–549 (2005).
He, R. et al. TSLP acts on infiltrating effector T cells to drive allergic skin inflammation. Proc. Natl. Acad. Sci. USA 105, 11875–11880 (2008).
Saenz, S.A., Taylor, B.C. & Artis, D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites. Immunol. Rev. 226, 172–190 (2008).
Kitajima, M., Lee, H.C., Nakayama, T. & Ziegler, S.F. TSLP enhances the function of helper type 2 cells. Eur. J. Immunol. 41, 1862–1871 (2011).
Yao, W. et al. Interleukin-9 is required for allergic airway inflammation mediated by the cytokine TSLP. Immunity 38, 360–372 (2013).
Angkasekwinai, P. et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J. Exp. Med. 204, 1509–1517 (2007).
Hurst, S.D. et al. 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, 443–453 (2002).
Fort, M.M. et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15, 985–995 (2001).
Dolgachev, V., Petersen, B.C., Budelsky, A.L., Berlin, A.A. & Lukacs, N.W. Pulmonary IL-17E (IL-25) production and IL-17RB+ myeloid cell-derived Th2 cytokine production are dependent upon stem cell factor-induced responses during chronic allergic pulmonary disease. J. Immunol. 183, 5705–5715 (2009).
Ballantyne, S.J. et al. Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J. Allergy Clin. Immunol. 120, 1324–1331 (2007).
Jung, J.S. et al. Association of IL-17RB gene polymorphism with asthma. Chest 135, 1173–1180 (2009).
Schmitz, J. et al. 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, 479–490 (2005).
Humphreys, N.E., Xu, D., Hepworth, M.R., Liew, F.Y. & Grencis, R.K. IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J. Immunol. 180, 2443–2449 (2008).
Townsend, M.J., Fallon, P.G., Matthews, D.J., Jolin, H.E. & McKenzie, A.N. T1/ST2-deficient mice demonstrate the importance of T1/ST2 in developing primary T helper cell type 2 responses. J. Exp. Med. 191, 1069–1076 (2000).
Oboki, K. et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc. Natl. Acad. Sci. USA 107, 18581–18586 (2010).
Neill, D.R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Hammad, H. & Lambrecht, B.N. Recent progress in the biology of airway dendritic cells and implications for understanding the regulation of asthmatic inflammation. J. Allergy Clin. Immunol. 118, 331–336 (2006).
Soumelis, V. et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680 (2002).
King, C., Tangye, S.G. & Mackay, C.R. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu. Rev. Immunol. 26, 741–766 (2008).
Veldhoen, M. et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9, 1341–1346 (2008).
Dardalhon, V. et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+IL-10+Foxp3− effector T cells. Nat. Immunol. 9, 1347–1355 (2008).
Shimbara, A. et al. IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J. Allergy Clin. Immunol. 105, 108–115 (2000).
Erpenbeck, V.J. et al. Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J. Allergy Clin. Immunol. 111, 1319–1327 (2003).
Reinhardt, R.L., Liang, H.E. & Locksley, R.M. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10, 385–393 (2009).
Liang, H.E. et al. Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 13, 58–66 (2012).
Hammad, H. et al. Inflammatory dendritic cells–not basophils–are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J. Exp. Med. 207, 2097–2111 (2010).
Gounni, A.S. et al. High-affinity IgE receptor on eosinophils is involved in defence against parasites. Nature 367, 183–186 (1994).
Li, L. & Krilis, S.A. Mast-cell growth and differentiation. Allergy 54, 306–312 (1999).
Kawabori, S., Kanai, N. & Tosho, T. Proliferative activity of mast cells in allergic nasal mucosa. Clin. Exp. Allergy 25, 173–178 (1995).
Carroll, N.G., Mutavdzic, S. & James, A.L. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Eur. Respir. J. 19, 879–885 (2002).
Lantz, C.S. et al. Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 392, 90–93 (1998).
Siracusa, M.C. et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477, 229–233 (2011).
Siracusa, M.C., Wojno, E.D. & Artis, D. Functional heterogeneity in the basophil cell lineage. Adv. Immunol. 115, 141–159 (2012).
Foster, P.S., Hogan, S.P., Ramsay, A.J., Matthaei, K.I. & Young, I.G. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med. 183, 195–201 (1996).
Mishra, A., Hogan, S.P., Lee, J.J., Foster, P.S. & Rothenberg, M.E. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J. Clin. Invest. 103, 1719–1727 (1999).
Rothenberg, M.E. & Hogan, S.P. The eosinophil. Annu. Rev. Immunol. 24, 147–174 (2006).
Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).
Loke, P. et al. IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 3, 7 (2002).
Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).
Spits, H. et al. Innate lymphoid cells - a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).
Fallon, P.G. et al. 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 (2006).
Moro, K. et al. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Price, A.E. et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl. Acad. Sci. USA 107, 11489–11494 (2010).
Koyasu, S. & Moro, K. Role of innate lymphocytes in infection and inflammation. Front. Immunol. 3, 101 (2012).
Walker, J.A., Barlow, J.L. & McKenzie, A.N. Innate lymphoid cells — how did we miss them? Nat. Rev. Immunol. 13, 75–87 (2013).
Saenz, S.A. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010).
Hoyler, T. et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37, 634–648 (2012).
Mjösberg, J. et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012).
Halim, T.Y. et al. Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity 37, 463–474 (2012).
Wong, S.H. et al. Transcription factor RORα is critical for nuocyte development. Nat. Immunol. 13, 229–236 (2012).
Mjösberg, J.M. et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. 12, 1055–1062 (2011).
Barnig, C. et al. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci. Transl. Med. 5, 174ra126 (2013).
Kondo, Y. et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int. Immunol. 20, 791–800 (2008).
Reed, C.E. & Kita, H. The role of protease activation of inflammation in allergic respiratory diseases. J. Allergy Clin. Immunol. 114, 997–1008, quiz 1009 (2004).
Gregory, L.G. & Lloyd, C.M. Orchestrating house dust mite-associated allergy in the lung. Trends Immunol. 32, 402–411 (2011).
Halim, T.Y., Krauss, R.H., Sun, A.C. & Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36, 451–463 (2012).
Kim, H.Y. et al. Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity. J. Allergy Clin. Immunol. 129, 216–227 (2012).
Chang, Y.J. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).
Voehringer, D., Reese, T.A., Huang, X., Shinkai, K. & Locksley, R.M. 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, 1435–1446 (2006).
Hsu, C.L., Neilsen, C.V. & Bryce, P.J. IL-33 is produced by mast cells and regulates IgE-dependent inflammation. PLoS ONE 5, e11944 (2010).
Kim, B.S. et al. TSLP Elicits IL-33-Independent Innate Lymphoid Cell Responses to Promote Skin Inflammation. Sci. Transl. Med. 5, 170ra116 (2013).
Klein Wolterink, R.G. et al. Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur. J. Immunol. 42, 1106–1116 (2012).
Barlow, J.L. et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J. Allergy Clin. Immunol. 129, 191–198 e191–194 (2012).
Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12, 1071–1077 (2011).
Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).
Fukuoka, A. et al. Identification of a novel type 2 innate immunocyte with the ability to enhance IgE production. Int. Immunol. advance online publication, doi:10.1093/intimm/dxs160 (14 February 2013).
Zaiss, D.M. et al. Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science 314, 1746 (2006).
Monticelli, L.A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).
Allen, J.E. & Maizels, R.M. Diversity and dialogue in immunity to helminths. Nat. Rev. Immunol. 11, 375–388 (2011).
Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host-microbiota mutualism. Science 325, 617–620 (2009).
Molofsky, A.B. et al. Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J. Exp. Med. 210, 535–549 (2013).
The authors declare no competing financial interests.
About this article
Cite this article
Licona-Limón, P., Kim, L., Palm, N. et al. TH2, allergy and group 2 innate lymphoid cells. Nat Immunol 14, 536–542 (2013). https://doi.org/10.1038/ni.2617
This article is cited by
Dendritic cells mediated by small extracellular vesicles derived from MSCs attenuated the ILC2 activity via PGE2 in patients with allergic rhinitis
Stem Cell Research & Therapy (2023)
Discovery of highly immunogenic spleen-resident FCGR3+CD103+ cDC1s differentiated by IL-33-primed ST2+ basophils
Cellular & Molecular Immunology (2023)
Nature Reviews Immunology (2023)
Early-life interactions between the microbiota and immune system: impact on immune system development and atopic disease
Nature Reviews Immunology (2023)
HTR2A agonists play a therapeutic role by restricting ILC2 activation in papain-induced lung inflammation
Cellular & Molecular Immunology (2023)