Innate lymphoid cells: major players in inflammatory diseases (original) (raw)

• Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).
  Article CAS PubMed Google Scholar
• Satoh-Takayama, N. et al. IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. J. Exp. Med. 207, 273–280 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
  Article CAS PubMed Google Scholar
• Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Luci, C. et al. Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10, 75–82 (2009).
  Article CAS PubMed Google Scholar
• Sanos, S. L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol. 10, 83–91 (2009).
  Article CAS PubMed Google Scholar
• Cupedo, T. et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat. Immunol. 10, 66–74 (2009).
  Article CAS PubMed Google Scholar
• 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).
  Article PubMed PubMed Central Google Scholar
• Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013). International experts in the field proposed a uniform nomenclature, in which ILCs are categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.
  Article CAS PubMed Google Scholar
• Carrega, P. et al. NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures. Nat. Commun. 6, 8280 (2015).
  Article CAS PubMed Google Scholar
• Kirchberger, S. et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210, 917–931 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• van Beek, J. J. P., Martens, A. W. J., Bakdash, G. & de Vries, I. J. M. Innate lymphoid cells in tumor immunity. Biomedicines 4, E7 (2015).
  Article CAS Google Scholar
• Dadi, S. et al. Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells. Cell 164, 365–377 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Dadi, S. & Li, M. O. Tissue-resident lymphocytes: sentinel of the transformed tissue. J. Immunother. Cancer 5, 41 (2017).
  Article PubMed PubMed Central Google Scholar
• Croxatto, D. et al. Group 3 innate lymphoid cells regulate neutrophil migration and function in human decidua. Mucosal Immunol. 9, 1372–1383 (2016).
  Article CAS PubMed Google Scholar
• Vacca, P. et al. NK cells and other innate lymphoid cells in hematopoietic stem cell transplantation. Front. Immunol. 7, 188 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Morita, H. et al. An interleukin-33-Mast cell-interleukin-2 axis suppresses papain-induced allergic inflammation by promoting regulatory T cell numbers. Immunity 43, 175–186 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Bartemes, K. R., Kephart, G. M., Fox, S. J. & Kita, H. Enhanced innate type 2 immune response in peripheral blood from patients with asthma. J. Allergy Clin. Immunol. 134, 671–678.e4 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Smith, S. G. et al. 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 (2016). In this cross-sectional study, analysis of blood and sputum ILC2s from asthmatic patients and controls showed that ILC2s can promote the persistence of airway eosinophilia in patients with severe asthma through uncontrolled localized production of the type 2 cytokines IL-5 and IL-13, despite high-dose oral corticosteroid therapy.
  Article CAS PubMed Google Scholar
• Christianson, C. A. et al. Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33. J. Allergy Clin. Immunol. 136, 59–68.e14 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, T. et al. Type 2 innate lymphoid cells: a novel biomarker of eosinophilic airway inflammation in patients with mild to moderate asthma. Respir. Med. 109, 1391–1396 (2015).
  Article PubMed Google Scholar
• Kabata, H. et al. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat. Commun. 4, 2675 (2013).
  Article CAS PubMed Google Scholar
• Halim, T. Y. F., 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).
  Article CAS PubMed Google Scholar
• Halim, T. Y. F. et al. Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40, 425–435 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Doherty, T. A. et al. STAT6 regulates natural helper cell proliferation during lung inflammation initiated by Alternaria. Am. J. Physiol. Lung Cell. Mol. Physiol. 303, L577–L588 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Chang, Y.-J. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Van Dyken, S. J. et al. Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells. Immunity 40, 414–424 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Stier, M. T. et al. Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. J. Allergy Clin. Immunol. 138, 814–824.e11 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, H.-C. et al. Thymic stromal lymphopoietin is induced by respiratory syncytial virus-infected airway epithelial cells and promotes a type 2 response to infection. J. Allergy Clin. Immunol. 130, 1187–1196.e5 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• 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.e1-4 (2012).
  Article CAS PubMed Google Scholar
• Martinez-Gonzalez, I. et al. Allergen-experienced group 2 innate lymphoid cells acquire memory-like properties and enhance allergic lung inflammation. Immunity 45, 198–208 (2016). In this study, the fate of lung ILC2s was examined upon allergen challenges, and some ILC2s were shown to persist long after the resolution of the inflammation and to respond to unrelated allergens more potently than naive ILC2s, suggesting memory-like properties of these allergen-experienced ILC2s.
  Article CAS PubMed Google Scholar
• Martinez-Gonzalez, I., Mathä, L., Steer, C. A. & Takei, F. Immunological memory of group 2 innate lymphoid cells. Trends Immunol. 38, 423–431 (2017).
  Article CAS PubMed Google Scholar
• de Kleer, I. M. et al. Perinatal activation of the interleukin-33 pathway promotes type 2 immunity in the developing lung. Immunity 45, 1285–1298 (2016).
  Article CAS PubMed Google Scholar
• Steer, C. A. et al. Group 2 innate lymphoid cell activation in the neonatal lung drives type 2 immunity and allergen sensitization. J. Allergy Clin. Immunol. http://dx.doi.org/10.1016/j.jaci.2016.12.984 (2017).
• Saluzzo, S. et al. First-breath-induced type 2 pathways shape the lung immune environment. Cell Rep. 18, 1893–1905 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Moffatt, M. F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Torgerson, D. G. et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat. Genet. 43, 887–892 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Savenije, O. E. M. et al. Interleukin-1 receptor-like 1 polymorphisms are associated with serum IL1RL1-a, eosinophils, and asthma in childhood. J. Allergy Clin. Immunol. 127, 750–756.e1-5 (2011).
  Article CAS PubMed Google Scholar
• Saravia, J. et al. Respiratory syncytial virus disease is mediated by age-variable IL-33. PLoS Pathog. 11, e1005217 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Hong, J. Y. et al. Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells. J. Allergy Clin. Immunol. 134, 429–439 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Sugita, K. et al. Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions via IL-13 in asthma. J. Allergy Clin. Immunol. https://doi.org/10.1016/j.jaci.2017.02.038 (2017).
  Article CAS Google Scholar
• Motomura, Y. et al. Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation. Immunity 40, 758–771 (2014).
  Article CAS PubMed Google Scholar
• Maazi, H. et al. ICOS:ICOS-ligand interaction is required for type 2 innate lymphoid cell function, homeostasis, and induction of airway hyperreactivity. Immunity 42, 538–551 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Harvima, I. T. et al. Molecular targets on mast cells and basophils for novel therapies. J. Allergy Clin. Immunol. 134, 530–544 (2014).
  Article CAS PubMed Google Scholar
• Xue, L. et al. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J. Allergy Clin. Immunol. 133, 1184–1194 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Chang, J. E., Doherty, T. A., Baum, R. & Broide, D. Prostaglandin D2 regulates human type 2 innate lymphoid cell chemotaxis. J. Allergy Clin. Immunol. 133, 899–901.e3 (2014).
  Article CAS PubMed Google Scholar
• Doherty, T. A. et al. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J. Allergy Clin. Immunol. 132, 205–213 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Barnig, C. et al. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci. Transl. Med. 5, 174ra26 (2013).
  Article CAS PubMed Google Scholar
• Drake, L. Y., Iijima, K. & Kita, H. Group 2 innate lymphoid cells and CD4+ T cells cooperate to mediate type 2 immune response in mice. Allergy 69, 1300–1307 (2014).
  Article CAS PubMed Google Scholar
• Mirchandani, A. S. et al. Type 2 innate lymphoid cells drive CD4+ Th2 cell responses. J. Immunol. 192, 2442–2448 (2014).
  Article CAS PubMed Google Scholar
• Oliphant, C. J. et al. MHCII-mediated dialog between group 2 innate lymphoid cells and CD4+ T cells potentiates type 2 immunity and promotes parasitic helminth expulsion. Immunity 41, 283–295 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Halim, T. Y. F. et al. Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses. Nat. Immunol. 17, 57–64 (2016).
  Article CAS PubMed Google Scholar
• Gold, M. J. et al. Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures. J. Allergy Clin. Immunol. 133, 1142–1148 (2014).
  Article CAS PubMed Google Scholar
• Van Dyken, S. J. et al. A tissue checkpoint regulates type 2 immunity. Nat. Immunol. 17, 1381–1387 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, H. Y. et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat. Med. 20, 54–61 (2014). This study using an obesity-induced mouse model of airway hyper-responsiveness suggested that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3s.
  Article CAS PubMed Google Scholar
• Everaere, L. et al. Innate lymphoid cells contribute to allergic airway disease exacerbation by obesity. J. Allergy Clin. Immunol. 138, 1309–1318.e11 (2016).
  Article CAS PubMed Google Scholar
• 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). This paper identified and described Lin − CD127+CD161+CRTH2+ ILC2s in humans as an innate source of type 2 cytokines and showed they are enriched in the nasal polyps of patients with chronic rhinosinusitis.
  Article CAS PubMed Google Scholar
• Bal, S. M. et al. 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, 636–645 (2016). In this study, plasticity between ILC2s and ILC1s and factors contributing to this plasticity are reported, as well as the role of this important mechanism in COPD and chronic rhinosinusitis with nasal polyps.
  Article CAS PubMed Google Scholar
• Lao-Araya, M., Steveling, E., Scadding, G. W., Durham, S. R. & Shamji, M. H. Seasonal increases in peripheral innate lymphoid type 2 cells are inhibited by subcutaneous grass pollen immunotherapy. J. Allergy Clin. Immunol. 134, 1193–1195.e4 (2014).
  Article PubMed Google Scholar
• Fan, D.-C. et al. Suppression of immunotherapy on group 2 innate lymphoid cells in allergic rhinitis. Chin. Med. J. 129, 2824–2828 (2016).
  Article PubMed PubMed Central Google Scholar
• Kearley, J. et al. Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection. Immunity 42, 566–579 (2015).
  Article CAS PubMed Google Scholar
• Silver, J. S. et al. Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. Nat. Immunol. 17, 626–635 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Ohne, Y. et al. IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat. Immunol. 17, 646–655 (2016).
  Article CAS PubMed Google Scholar
• Li, D. et al. 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, 1422–1432.e11 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Hams, E. et al. IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. Proc. Natl Acad. Sci. USA 111, 367–372 (2014).
  Article CAS PubMed Google Scholar
• Wohlfahrt, T. et al. Type 2 innate lymphoid cell counts are increased in patients with systemic sclerosis and correlate with the extent of fibrosis. Ann. Rheum. Dis. 75, 623–626 (2016). This study showed that ILC2 counts were elevated in patients with systemic sclerosis and correlated with the extent of skin fibrosis and the presence of interstitial lung disease, providing evidence for a profibrotic effect of ILC2s in the disease.
  Article CAS PubMed Google Scholar
• Monticelli, L. A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Bernink, J. H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–229 (2013). This paper identified and described T-bet-expressing and IFNγ-producing ILC1s, detailed their plasticity with RORγt+ ILC3s and showed they are enriched in the inflamed intestines of patients with Crohn's disease.
  Article CAS PubMed Google Scholar
• Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Hepworth, M. R. et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498, 113–117 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Bernink, J. H. et al. Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43, 146–160 (2015).
  Article CAS PubMed Google Scholar
• Hoorweg, K. et al. Functional differences between human NKp44− and NKp44+ RORC+ innate lymphoid cells. Front. Immunol. 3, 72 (2012).
  Article PubMed PubMed Central Google Scholar
• Hanash, A. M. et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37, 339–350 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Aparicio-Domingo, P. et al. Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage. J. Exp. Med. 212, 1783–1791 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Hepworth, M. R. et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 348, 1031–1035 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Klose, C. S. N. et al. A T-bet gradient controls the fate and function of CCR6−RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013).
  Article CAS PubMed Google Scholar
• Reynders, A. et al. Identity, regulation and in vivo function of gut NKp46+RORγt+ and NKp46+RORγt− lymphoid cells. EMBO J. 30, 2934–2947 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Klose, C. S. N. et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340–356 (2014).
  Article CAS PubMed Google Scholar
• Song, C. et al. Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. J. Exp. Med. 212, 1869–1882 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Rankin, L. C. et al. Complementarity and redundancy of IL-22-producing innate lymphoid cells. Nat. Immunol. 17, 179–186 (2016). In this study, NCR+ ILC3 cells were found to be redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells, showing the complementarity and redundancy of intestinal ILC3s and adaptive lymphocytes to ensure gut homeostasis.
  Article CAS PubMed Google Scholar
• Powell, N. et al. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 37, 674–684 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Geiger, T. L. et al. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J. Exp. Med. 211, 1723–1731 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Abt, M. C. et al. Innate immune defenses mediated by two ILC subsets are critical for protection against acute clostridium difficile infection. Cell Host Microbe 18, 27–37 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Cua, D. J. & Tato, C. M. Innate IL-17-producing cells: the sentinels of the immune system. Nat. Rev. Immunol. 10, 479–489 (2010).
  Article CAS PubMed Google Scholar
• Gladiator, A., Wangler, N., Trautwein-Weidner, K. & LeibundGut-Landmann, S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J. Immunol. 190, 521–525 (2013).
  Article CAS PubMed Google Scholar
• Huang, Y. et al. IL-25-responsive, lineage-negative KLRG1hi cells are multipotential “inflammatory” type 2 innate lymphoid cells. Nat. Immunol. 16, 161–169 (2015).
  Article CAS PubMed Google Scholar
• Oeser, K., Schwartz, C. & Voehringer, D. Conditional IL-4/IL-13-deficient mice reveal a critical role of innate immune cells for protective immunity against gastrointestinal helminths. Mucosal Immunol. 8, 672–682 (2015).
  Article CAS PubMed Google Scholar
• Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Wilhelm, C. et al. Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection. J. Exp. Med. 213, 1409–1418 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Peters, C. P., Mjösberg, J. M., Bernink, J. H. & Spits, H. Innate lymphoid cells in inflammatory bowel diseases. Immunol. Lett. 172, 124–131 (2016).
  Article CAS PubMed Google Scholar
• Geremia, A. et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).
  Article CAS PubMed Google Scholar
• Lee, J. S. et al. Interleukin-23-Independent IL-17 production regulates intestinal epithelial permeability. Immunity 43, 727–738 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Fuchs, A. et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity 38, 769–781 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Li, J., Doty, A. L., Iqbal, A. & Glover, S. C. The differential frequency of lineage−CRTH2−CD45+NKp44−CD117−CD127+ILC subset in the inflamed terminal ileum of patients with Crohn's disease. Cell. Immunol. 304–305, 63–68 (2016).
  Article CAS PubMed Google Scholar
• Takayama, T. et al. Imbalance of NKp44+NKp46− and NKp44−NKp46+ natural killer cells in the intestinal mucosa of patients with Crohn's disease. Gastroenterology 139, 882–892.e1-3 (2010).
  Article CAS PubMed Google Scholar
• Vonarbourg, C. et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Lim, A. I. et al. IL-12 drives functional plasticity of human group 2 innate lymphoid cells. J. Exp. Med. 213, 569–583 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Lo, B. C. et al. The orphan nuclear receptor RORα and group 3 innate lymphoid cells drive fibrosis in a mouse model of Crohn's disease. Sci. Immunol. 1, eaaf8864 (2016).
  Article PubMed PubMed Central Google Scholar
• Doherty, T. A. et al. Group 2 innate lymphocytes (ILC2) are enriched in active eosinophilic esophagitis. J. Allergy Clin. Immunol. 136, 792–794.e3 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Simon, D., Radonjic-Hösli, S., Straumann, A., Yousefi, S. & Simon, H.-U. Active eosinophilic esophagitis is characterized by epithelial barrier defects and eosinophil extracellular trap formation. Allergy 70, 443–452 (2015).
  Article CAS PubMed Google Scholar
• Dyring-Andersen, B. et al. Increased number and frequency of group 3 innate lymphoid cells in nonlesional psoriatic skin. Br. J. Dermatol. 170, 609–616 (2014).
  Article CAS PubMed Google Scholar
• Teunissen, M. B. M. et al. Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR+ ILC3 in lesional skin and blood of psoriasis patients. J. Invest. Dermatol. 134, 2351–2360 (2014). In this paper, increased proportions of IL-22-producing NCR+ ILC3s were present in the lesional skin and peripheral blood of psoriasis patients, suggesting a role of NCR+ ILC3s in psoriasis pathology.
  Article CAS PubMed Google Scholar
• Villanova, F. et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J. Invest. Dermatol. 134, 984–991 (2014).
  Article CAS PubMed Google Scholar
• Roediger, B. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat. Immunol. 14, 564–573 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, B. S. et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci. Transl. Med. 5, 170ra16 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Salimi, M. et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J. Exp. Med. 210, 2939–2950 (2013). Using human skin biopsies from atopic patients and mouse models, this paper identified a role for ILC2s in the pathogenesis of atopic dermatitis and detailed the signalling pathways involved.
  Article CAS PubMed PubMed Central Google Scholar
• Soumelis, V. et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680 (2002).
  Article CAS PubMed Google Scholar
• Savinko, T. et al. IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J. Invest. Dermatol. 132, 1392–1400 (2012).
  Article CAS PubMed Google Scholar
• Wang, Y.-H. et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J. Exp. Med. 204, 1837–1847 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Saunders, S. P. et al. 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, 482–491 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, L.-Y. et al. Protein palmitoylation by ZDHHC13 protects skin against microbial-driven dermatitis. J. Invest. Dermatol. https://doi.org/10.1016/j.jid.2016.12.011 (2013).
  Article CAS Google Scholar
• Kim, B. S. et al. Basophils promote innate lymphoid cell responses in inflamed skin. J. Immunol. 193, 3717–3725 (2014).
  Article CAS PubMed Google Scholar
• Tang, A., Amagai, M., Granger, L. G., Stanley, J. R. & Udey, M. C. Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin. Nature 361, 82–85 (1993).
  Article CAS PubMed Google Scholar
• Trautmann, A. et al. The differential fate of cadherins during T-cell-induced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis. J. Invest. Dermatol. 117, 927–934 (2001).
  Article CAS PubMed Google Scholar
• Salimi, M. et al. Group 2 innate lymphoid cells express functional NKp30 receptor inducing type 2 cytokine production. J. Immunol. 196, 45–54 (2016).
  Article CAS PubMed Google Scholar
• Michalek, I. M., Loring, B. & John, S. M. A systematic review of worldwide epidemiology of psoriasis. J. Eur. Acad. Dermatol. Venereol 31, 205–212 (2017).
  Article CAS PubMed Google Scholar
• Bowcock, A. M. & Krueger, J. G. Getting under the skin: the immunogenetics of psoriasis. Nat. Rev. Immunol. 5, 699–711 (2005).
  Article CAS PubMed Google Scholar
• Austin, L. M., Ozawa, M., Kikuchi, T., Walters, I. B. & Krueger, J. G. The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-γ, interleukin-2, and tumor necrosis factor-α, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J. Invest. Dermatol. 113, 752–759 (1999).
  Article CAS PubMed Google Scholar
• Pantelyushin, S. et al. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J. Clin. Invest. 122, 2252–2256 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Li, Z. et al. Epidermal Notch1 recruits RORγ+ group 3 innate lymphoid cells to orchestrate normal skin repair. Nat. Commun. 7, 11394 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Rak, G. D. et al. IL-33-Dependent group 2 innate lymphoid cells promote cutaneous wound healing. J. Invest. Dermatol. 136, 487–496 (2016). This study demonstrated that IL-33-responsive ILC2s promote the restoration of skin integrity after injury.
  Article CAS PubMed PubMed Central Google Scholar
• Duffin, R. et al. Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science 351, 1333–1338 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Dalli, J., Colas, R. A., Arnardottir, H. & Serhan, C. N. Vagal regulation of group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution. Immunity 46, 92–105 (2017).
  Article CAS PubMed PubMed Central Google Scholar
• Cols, M. et al. Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency. J. Allergy Clin. Immunol. 137, 1206–1215.e1-6 (2016).
  Article CAS PubMed Google Scholar
• Roan, F. et al. CD4+ group 1 innate lymphoid cells (ILC) form a functionally distinct ILC subset that is increased in systemic sclerosis. J. Immunol. 196, 2051–2062 (2016).
  Article CAS PubMed Google Scholar
• De Lauretis, A. et al. Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J. Rheumatol 40, 435–446 (2013).
  Article CAS PubMed Google Scholar
• Khanna, D. et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 387, 2630–2640 (2016).
  Article CAS PubMed Google Scholar
• Leijten, E. F. A. et al. Brief report: enrichment of activated group 3 innate lymphoid cells in psoriatic arthritis synovial fluid. Arthritis Rheumatol. 67, 2673–2678 (2015).
  Article PubMed Google Scholar
• Triggianese, P. et al. Evidence of IL-17 producing innate lymphoid cells in peripheral blood from patients with enteropathic spondyloarthritis. Clin. Exp. Rheumatol 34, 1085–1093 (2016).
  PubMed Google Scholar
• Rodríguez-Carrio, J. et al. Brief report: altered innate lymphoid cell subsets in human lymph node biopsy specimens obtained during the at-Risk and earliest phases of rheumatoid arthritis. Arthritis Rheumatol. 69, 70–76 (2017).
  Article CAS PubMed Google Scholar
• Lin, Y. C. et al. Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis. Ann. Clin. Transl Neurol. 2, 445–455 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Perry, J. S. A. et al. Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis. Sci. Transl. Med. 4, 145ra106 (2012).
  Article CAS PubMed Google Scholar
• Gillard, G. O., Saenz, S. A., Huss, D. J. & Fontenot, J. D. Circulating innate lymphoid cells are unchanged in response to DAC HYP therapy. J. Neuroimmunol. 294, 41–45 (2016).
  Article CAS PubMed Google Scholar
• Gross, C. C. et al. Distinct pattern of lesion distribution in multiple sclerosis is associated with different circulating T-helper and helper-like innate lymphoid cell subsets. Mult. Scler. 23, 1025–1030 (2016).
  Article CAS PubMed Google Scholar
• Gross, C. C. et al. Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis. Neurol. Neuroimmunol. Neuroinflamm 3, e289 (2016).
  Article PubMed PubMed Central Google Scholar
• Hatfield, J. K. & Brown, M. A. Group 3 innate lymphoid cells accumulate and exhibit disease-induced activation in the meninges in EAE. Cell Immunol. 297, 69–79 (2015).
  Article CAS PubMed Google Scholar
• Gadani, S. P., Smirnov, I., Smith, A. T., Overall, C. C. & Kipnis, J. Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury. J. Exp. Med. 214, 285–296 (2017).
  Article CAS PubMed Google Scholar
• Neumann, K. et al. A proinflammatory role of type 2 innate lymphoid cells in murine immune-mediated hepatitis. J. Immunol. 198, 128–137 (2017).
  Article CAS PubMed Google Scholar
• McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013). In this study, the profibrotic effects of IL-33 are shown to be related to the activation and expansion of liver-resident ILC2s, and ILC2-derived IL-13 was found to be a critical downstream cytokine of IL-33-dependent pathologic tissue remodelling and fibrosis.
  Article CAS PubMed PubMed Central Google Scholar
• Yang, Z., Tang, T., Wei, X., Yang, S. & Tian, Z. Type 1 innate lymphoid cells contribute to the pathogenesis of chronic hepatitis B. Innate Immun. 21, 665–673 (2015).
  Article CAS PubMed Google Scholar
• Vély, F. et al. Evidence of innate lymphoid cell redundancy in humans. Nat. Immunol. 17, 1291–1299 (2016). This study showed that there is a selective ILC deficiency in patients with severe combined immunodeficiency after haematopoietic stem cell transplantation and suggested that ILCs might be dispensable in natural conditions if T cells are present and B cell function is preserved.
  Article CAS PubMed PubMed Central Google Scholar
• Fischer, A. & Rausell, A. Primary immunodeficiencies suggest redundancy within the human immune system. Sci. Immunol. 1, eaah5861 (2016).
  Article PubMed Google Scholar