Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Sensing of physiological regulators by innate lymphoid cells

Abstract

Maintenance of homeostasis and immune protection rely  on the coordinated action of different physiological systems. Bidirectional communication between the immune system and physiological systems is required to sense and restore any disruption of equilibrium. Recent transcriptomic analyses of innate lymphoid cells (ILCs) from different tissues have revealed that ILCs express a large array of receptors involved in the recognition of neuropeptides, hormones and metabolic signals. ILCs rapidly secrete effector cytokines that are central in the development and activation of early immune responses, but they also constitutively secrete mediators that are important for tissue homeostasis. To achieve these functions effectively, ILCs integrate intrinsic and extrinsic signals that modulate their constitutive and induced activity. Disruption of the regulation of ILCs by physiological regulators leads to altered immune responses with harmful consequences for the organism. An understanding of these complex interactions between the immune system and physiological mediators is crucial to decipher the events leading to the protective versus pathological effects of these cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Chrousos, G. P. & Gold, P. W. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267, 1244–1252 (1992).

    CAS  PubMed  Google Scholar 

  2. Medzhitov, R. Inflammation 2010: new adventures of an old flame. Cell 140, 771–776 (2010).

    CAS  PubMed  Google Scholar 

  3. Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).

    CAS  PubMed  Google Scholar 

  4. Ishizuka, I. E. et al. Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue-inducer cell lineage. Nat. Immunol. 17, 269–276 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Constantinides, M. G., McDonald, B. D., Verhoef, P. A. & Bendelac, A. A committed precursor to innate lymphoid cells. Nature 508, 397–401 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 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).

    CAS  PubMed  Google Scholar 

  7. Seillet, C. et al. Differential requirement for Nfil3 during NK cell development. J. Immunol. 192, 2667–2676 (2014).

    CAS  PubMed  Google Scholar 

  8. Yu, Y. et al. Single-cell RNA-seq identifies a PD-1(hi) ILC progenitor and defines its development pathway. Nature 539, 102–106 (2016).

    CAS  PubMed  Google Scholar 

  9. Seillet, C. et al. Deciphering the innate lymphoid cell transcriptional program. Cell Rep. 17, 436–447 (2016).

    CAS  PubMed  Google Scholar 

  10. Bando, J. K., Liang, H.-E. & Locksley, R. M. Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. Nat. Immunol. 16, 153–160 (2015).

    CAS  PubMed  Google Scholar 

  11. Gasteiger, G., Fan, X., Dikiy, S., Lee, S. Y. & Rudensky, A. Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang, Y. et al. IL-25-responsive, lineage-negative KLRG1(hi) cells are multipotential ‘inflammatory’ type 2 innate lymphoid cells. Nat. Immunol. 16, 161–169 (2015).

    CAS  PubMed  Google Scholar 

  13. Stier, M. T. et al. IL-33 promotes the egress of group 2 innate lymphoid cells from the bone marrow. J. Exp. Med. 215, 263–281 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Huang, Y. et al. S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense. Science 359, 114–119 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ricardo-Gonzalez, R. R. et al. Tissue signals imprint ILC2 identity with anticipatory function. Nat. Immunol. 10, 1093–1099 (2018).

    Google Scholar 

  16. Gury-BenAri, M. et al. The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell 166, 1231–1246.e13 (2016).

    CAS  PubMed  Google Scholar 

  17. Monticelli, L. A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sawa, S. et al. RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320–326 (2011).

    CAS  PubMed  Google Scholar 

  19. Weizman, O. E. et al. ILC1 confer early host protection at initial sites of viral infection. Cell 171, 795–808 e712 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Jiao, Y., Huntington, N. D., Belz, G. T. & Seillet, C. Type 1 innate lymphoid cell biology: lessons learnt from natural killer cells. Front Immunol. 7, 426 (2016).

    PubMed  PubMed Central  Google Scholar 

  22. Boulenouar, S. et al. Adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted cytotoxicity. Immunity 46, 273–286 (2017).

    CAS  PubMed  Google Scholar 

  23. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Seillet, C., Belz, G. T. & Mielke, L. A. Complexity of cytokine network regulation of innate lymphoid cells in protective immunity. Cytokine 70, 1–10 (2014).

    CAS  PubMed  Google Scholar 

  25. Chang, Y.-J. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Behnsen, J. et al. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity 40, 262–273 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Pickard, J. M. et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 514, 638–641 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Satoh-Takayama, N. et al. The chemokine receptor CXCR6 controls the functional topography of interleukin-22 producing intestinal innate lymphoid cells. Immunity 41, 776–788 (2014).

    CAS  PubMed  Google Scholar 

  30. Rankin, L. C. et al. The transcription factor T-bet is essential for the development of NKp46(+) innate lymphocytes via the Notch pathway. Nat. Immunol. 14, 389–395 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Sawada, M., Itoh, Y., Suzumura, A. & Marunouchi, T. Expression of cytokine receptors in cultured neuronal and glial cells. Neurosci. Lett. 160, 131–134 (1993).

    CAS  PubMed  Google Scholar 

  32. Neumann, H. et al. Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. J. Neurosci. 22, 854–862 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Gougeon, P. Y. et al. The pro-inflammatory cytokines IL-1beta and TNFalpha are neurotrophic for enteric neurons. J. Neurosci. 33, 3339–3351 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Klose, C. S. N. et al. The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549, 282–286 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Howard, A. D. et al. Identification of receptors for neuromedin U and its role in feeding. Nature 406, 70–74 (2000).

    CAS  PubMed  Google Scholar 

  36. Cardoso, V. et al. Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wallrapp, A. et al. The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549, 351–356 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Moriyama, M. et al. The neuropeptide neuromedin U promotes inflammation by direct activation of mast cells. J. Exp. Med. 202, 217–224 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Mashaghi, A. et al. Neuropeptide substance P and the immune response. Cell Mol. Life Sci. 73, 4249–4264 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Feistritzer, C. et al. Natural killer cell functions mediated by the neuropeptide substance P. Regul. Pept. 116, 119–126 (2003).

    CAS  PubMed  Google Scholar 

  41. Lang, K., Drell, T. L., Niggemann, B., Zanker, K. S. & Entschladen, F. Neurotransmitters regulate the migration and cytotoxicity in natural killer cells. Immunol. Lett. 90, 165–172 (2003).

    CAS  PubMed  Google Scholar 

  42. Monaco-Shawver, L. et al. Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor. J. Leukoc. Biol. 89, 113–125 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Lighvani, S., Huang, X., Trivedi, P. P., Swanborg, R. H. & Hazlett, L. D. Substance P regulates natural killer cell interferon-gamma production and resistance to Pseudomonas aeruginosa infection. Eur. J. Immunol. 35, 1567–1575 (2005).

    CAS  PubMed  Google Scholar 

  44. Sears, M. R. et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 336, 1391–1396 (1990).

    CAS  PubMed  Google Scholar 

  45. Milano, C. A. et al. Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science 264, 582–586 (1994).

    CAS  PubMed  Google Scholar 

  46. Sun, Z. et al. Norepinephrine inhibits the cytotoxicity of NK92MI cells via the beta2adrenoceptor/cAMP/PKA/pCREB signaling pathway. Mol. Med. Rep. 17, 8530–8535 (2018).

    CAS  PubMed  Google Scholar 

  47. De Lorenzo, B. H., de Oliveira Marchioro, L., Greco, C. R. & Suchecki, D. Sleep-deprivation reduces NK cell number and function mediated by beta-adrenergic signalling. Psychoneuroendocrinology 57, 134–143 (2015).

    PubMed  Google Scholar 

  48. Logan, R. W., Arjona, A. & Sarkar, D. K. Role of sympathetic nervous system in the entrainment of circadian natural-killer cell function. Brain Behav. Immun. 25, 101–109 (2011).

    CAS  PubMed  Google Scholar 

  49. Moriyama, S. et al. beta2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359, 1056–1061 (2018).

    CAS  PubMed  Google Scholar 

  50. Wang, H. et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).

    CAS  PubMed  Google Scholar 

  51. Borovikova, L. V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ramon, S. et al. The protectin PCTR1 is produced by human M2 macrophages and enhances resolution of infectious inflammation. Am. J. Pathol. 186, 962–973 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Said, S. I. & Rosenberg, R. N. Vasoactive intestinal polypeptide: abundant immunoreactivity in neural cell lines and normal nervous tissue. Science 192, 907–908 (1976).

    CAS  PubMed  Google Scholar 

  55. Aton, S. J., Colwell, C. S., Harmar, A. J., Waschek, J. & Herzog, E. D. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat. Neurosci. 8, 476–483 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ibrahim, H., Barrow, P. & Foster, N. Transcriptional modulation by VIP: a rational target against inflammatory disease. Clin. Epigenetics 2, 213–222 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Delgado, M. & Ganea, D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids 45, 25–39 (2013).

    CAS  PubMed  Google Scholar 

  58. Nussbaum, J. C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Talbot, S. et al. Silencing nociceptor neurons reduces allergic airway inflammation. Neuron 87, 341–354 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Hoegger, M. J. et al. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science 345, 818–822 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Sui, P. et al. Pulmonary neuroendocrine cells amplify allergic asthma responses. Science 360, eaan8546 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. Xiang, Y. Y. et al. A GABAergic system in airway epithelium is essential for mucus overproduction in asthma. Nat. Med. 13, 862–867 (2007).

    CAS  PubMed  Google Scholar 

  63. Ibiza, S. et al. Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Nature 535, 440–443 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Ruzek, M. C., Pearce, B. D., Miller, A. H. & Biron, C. A. Endogenous glucocorticoids protect against cytokine-mediated lethality during viral infection. J. Immunol. 162, 3527–3533 (1999).

    CAS  PubMed  Google Scholar 

  65. Bereshchenko, O., Bruscoli, S. & Riccardi, C. Glucocorticoids, sex hormones, and immunity. Front Immunol. 9, 1332 (2018).

    PubMed  PubMed Central  Google Scholar 

  66. Quatrini, L. et al. Endogenous glucocorticoids control host resistance to viral infection through the tissue-specific regulation of PD-1 expression on NK cells. Nat. Immunol. 19, 954–962 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Quatrini, L. et al. Host resistance to endotoxic shock requires the neuroendocrine regulation of group 1 innate lymphoid cells. J. Exp. Med. 214, 3531–3541 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kovats, S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol. 294, 63–69 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).

    CAS  PubMed  Google Scholar 

  70. Sorachi, K., Kumagai, S., Sugita, M., Yodoi, J. & Imura, H. Enhancing effect of 17 beta-estradiol on human NK cell activity. Immunol. Lett. 36, 31–35 (1993).

    CAS  PubMed  Google Scholar 

  71. Souza, S. S. et al. Influence of menstrual cycle on NK activity. J. Reprod. Immunol. 50, 151–159 (2001).

    CAS  PubMed  Google Scholar 

  72. Hao, S., Li, P., Zhao, J., Hu, Y. & Hou, Y. 17beta-estradiol suppresses cytotoxicity and proliferative capacity of murine splenic NK1.1+ cells. Cell. Mol. Immunol. 5, 357–364 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Bartemes, K., Chen, C. C., Iijima, K., Drake, L. & Kita, H. IL-33-responsive group 2 innate lymphoid cells are regulated by female sex hormones in the uterus. J. Immunol. 200, 229–236 (2018).

    CAS  PubMed  Google Scholar 

  74. Laffont, S. et al. Androgen signaling negatively controls group 2 innate lymphoid cells. J. Exp. Med. 214, 1581–1592 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Townsend, E. A., Miller, V. M. & Prakash, Y. S. Sex differences and sex steroids in lung health and disease. Endocr. Rev. 33, 1–47 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Cephus, J. Y. et al. Testosterone attenuates group 2 innate lymphoid cell-mediated airway inflammation. Cell Rep. 21, 2487–2499 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Czarnewski, P., Das, S., Parigi, S. M. & Villablanca, E. J. Retinoic acid and its role in modulating intestinal innate immunity. Nutrients 9, 68 (2017).

  78. Mora, J. R., Iwata, M. & von Andrian, U. H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat. Rev. Immunol. 8, 685–698 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Dimitrov, V. & White, J. H. Vitamin D signaling in intestinal innate immunity and homeostasis. Mol. Cell Endocrinol. 453, 68–78 (2017).

    CAS  PubMed  Google Scholar 

  80. van de Pavert, S. A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).

    PubMed  PubMed Central  Google Scholar 

  81. Mielke, L. A. et al. Retinoic acid expression associates with enhanced IL-22 production by gammadelta T cells and innate lymphoid cells and attenuation of intestinal inflammation. J. Exp. Med. 210, 1117–1124 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kim, M. H., Taparowsky, E. J. & Kim, C. H. Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut. Immunity 43, 107–119 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    CAS  PubMed  Google Scholar 

  85. Chen, J., Waddell, A., Lin, Y. D. & Cantorna, M. T. Dysbiosis caused by vitamin D receptor deficiency confers colonization resistance to Citrobacter rodentium through modulation of innate lymphoid cells. Mucosal Immunol. 8, 618–626 (2015).

    CAS  PubMed  Google Scholar 

  86. Konya, V. et al. Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells. J. Allergy Clin. Immunol. 141, 279–292 (2018).

    CAS  PubMed  Google Scholar 

  87. Ruiter, B., Patil, S. U. & Shreffler, W. G. Vitamins A and D have antagonistic effects on expression of effector cytokines and gut-homing integrin in human innate lymphoid cells. Clin. Exp. Allergy 45, 1214–1225 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Denison, M. S. & Nagy, S. R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43, 309–334 (2003).

    CAS  PubMed  Google Scholar 

  89. Stockinger, B., Di Meglio, P., Gialitakis, M. & Duarte, J. H. The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev. Immunol. 32, 403–432 (2014).

    CAS  PubMed  Google Scholar 

  90. Fernandez-Salguero, P. et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268, 722–726 (1995).

    CAS  PubMed  Google Scholar 

  91. Lee, J. S. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 13, 144–151 (2011).

    PubMed  PubMed Central  Google Scholar 

  92. Kiss, E. A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).

    CAS  PubMed  Google Scholar 

  93. Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012).

    CAS  PubMed  Google Scholar 

  94. Schiering, C. et al. Feedback control of AHR signalling regulates intestinal immunity. Nature 542, 242–245 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Hughes, T. et al. The transcription factor AHR prevents the differentiation of a stage 3 innate lymphoid cell subset to natural killer cells. Cell Rep. 8, 150–162 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Conlon, M. A. & Bird, A. R. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7, 17–44 (2014).

    PubMed  PubMed Central  Google Scholar 

  97. Zelante, T. et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39, 372–385 (2013).

    CAS  PubMed  Google Scholar 

  98. Sanos, S. L. et al. RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol. 10, 83–91 (2009).

    CAS  PubMed  Google Scholar 

  99. Gomez de Aguero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016).

    PubMed  Google Scholar 

  100. Shimizu, T. Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu Rev. Pharmacol. Toxicol. 49, 123–150 (2009).

    CAS  PubMed  Google Scholar 

  101. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. von Moltke, J. et al. Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s. J. Exp. Med. 214, 27–37 (2017).

    Google Scholar 

  103. Lund, S. J. et al. Leukotriene C4 potentiates IL-33-induced group 2 innate lymphoid cell activation and lung inflammation. J. Immunol. 199, 1096–1104 (2017).

    CAS  PubMed  Google Scholar 

  104. Salimi, M. et al. Cysteinyl leukotriene E4 activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2 and epithelial cytokines. J. Allergy Clin. Immunol. 140, 1090–1100 e1011 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Yokomizo, T., Nakamura, M. & Shimizu, T. Leukotriene receptors as potential therapeutic targets. J. Clin. Invest. 128, 2691–2701 (2018).

    PubMed  PubMed Central  Google Scholar 

  106. Kim, A. S. & Doherty, T. A. New and emerging therapies for asthma. Ann. Allergy Asthma Immunol. 116, 14–17 (2016).

    PubMed  PubMed Central  Google Scholar 

  107. Zhou, Y. et al. Prostaglandin E2 inhibits group 2 innate lymphoid cell activation and allergic airway inflammation through E-prostanoid 4-cyclic adenosine monophosphate signaling. Front Immunol. 9, 501 (2018).

    PubMed  PubMed Central  Google Scholar 

  108. Zhou, W. et al. Prostaglandin I2 signaling and inhibition of group 2 innate lymphoid cell responses. Am. J. Respir. Crit. Care Med. 193, 31–42 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Wojno, E. D. et al. The prostaglandin D(2) receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung. Mucosal Immunol. 8, 1313–1323 (2015).

    PubMed  Google Scholar 

  110. 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 e893 (2014).

    CAS  PubMed  Google Scholar 

  111. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Nagata, K. et al. Selective expression of a novel surface molecule by human Th2 cells in vivo. J. Immunol. 162, 1278–1286 (1999).

    CAS  PubMed  Google Scholar 

  113. Mjosberg, 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).

    PubMed  Google Scholar 

  114. Boyce, J. A. Mast cells and eicosanoid mediators: a system of reciprocal paracrine and autocrine regulation. Immunol. Rev. 217, 168–185 (2007).

    CAS  PubMed  Google Scholar 

  115. Fajt, M. L. et al. Prostaglandin D(2) pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J. Allergy Clin. Immunol. 131, 1504–1512 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    Google Scholar 

  117. Maric, J. et al. Prostaglandin E2 suppresses human group 2 innate lymphoid cell function. J. Allergy Clin. Immunol. 141, 1761–1773 e1766 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Duffin, R. et al. Prostaglandin E(2) constrains systemic inflammation through an innate lymphoid cell-IL-22 axis. Science 351, 1333–1338 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Claar, D., Hartert, T. V. & Peebles, R. S. Jr. The role of prostaglandins in allergic lung inflammation and asthma. Expert Rev. Respir. Med. 9, 55–72 (2015).

    CAS  PubMed  Google Scholar 

  120. Rumzhum, N. N. & Ammit, A. J. Cyclooxygenase 2: its regulation, role and impact in airway inflammation. Clin. Exp. Allergy 46, 397–410 (2016).

    CAS  PubMed  Google Scholar 

  121. Hara, S. Prostaglandin terminal synthases as novel therapeutic targets. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 93, 703–723 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors apologize to all investigators whose works were not cited in this article due to space limitations. We are grateful to Kylie Luong for helpful comments and preparation of the manuscript. The figure was drawn using Servier Medical Art (https://smart.servier.com) and modified by the authors under the terms of the Creative Commons Attribution 3.0 Unported License. C.S. was supported by grants and fellowships from the National Health and Medical Research Council (NHMRC) of Australia (APP1165443) and the Australian Research Career Development Fellowship (APP1123000). N.J. was supported by Grant 1163990 awarded through the 2018 Priority-driven Collaborative Cancer Research Scheme and cofunded by Cancer Australia and Cure Cancer. This work was made possible through the Victorian State Government Operational Infrastructure Support and the Australian Government NHMRC IRIIS.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Cyril Seillet.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seillet, C., Jacquelot, N. Sensing of physiological regulators by innate lymphoid cells. Cell Mol Immunol 16, 442–451 (2019). https://doi.org/10.1038/s41423-019-0217-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-019-0217-1

Keywords

This article is cited by

Search

Quick links