Innate Lymphoid Cells: 10 Years On

Innate lymphoid cells (ILCs) are lymphocytes that do not express the type of diversified antigen receptors expressed on T cells and B cells. ILCs are largely tissue-resident cells and are deeply integrated into the fabric of tissues. The discovery and investigation of ILCs over the past decade has changed our perception of immune regulation and how the immune system contributes to the maintenance of tissue homeostasis. We now know that cytokine-producing ILCs contribute to multiple immune pathways by, for example, sustaining appropriate immune responses to commensals and pathogens at mucosal barriers, potentiating adaptive immunity, and regulating tissue inflammation. Critically, the biology of ILCs also extends beyond classical immunology to metabolic homeostasis, tissue remodeling, and dialog with the nervous system. The last 10 years have also contributed to our greater understanding of the transcriptional networks that regulate lymphocyte commitment and delineation. This, in conjunction with the recent advances in our understanding of the influence of local tissue microenvironments on the plasticity and function of ILCs, has led to a re-evaluation of their existing categorization. In this review, we distill the advances in ILC biology over the past decade to refine the nomenclature of ILCs and highlight the importance of ILCs in tissue homeostasis, morphogenesis, metabolism, repair, and regeneration. Innate lymphoid cells (ILCs) are lymphocytes that do not express the type of diversified antigen receptors expressed on T cells and B cells. ILCs are largely tissue-resident cells and are deeply integrated into the fabric of tissues. The discovery and investigation of ILCs over the past decade has changed our perception of immune regulation and how the immune system contributes to the maintenance of tissue homeostasis. We now know that cytokine-producing ILCs contribute to multiple immune pathways by, for example, sustaining appropriate immune responses to commensals and pathogens at mucosal barriers, potentiating adaptive immunity, and regulating tissue inflammation. Critically, the biology of ILCs also extends beyond classical immunology to metabolic homeostasis, tissue remodeling, and dialog with the nervous system. The last 10 years have also contributed to our greater understanding of the transcriptional networks that regulate lymphocyte commitment and delineation. This, in conjunction with the recent advances in our understanding of the influence of local tissue microenvironments on the plasticity and function of ILCs, has led to a re-evaluation of their existing categorization. In this review, we distill the advances in ILC biology over the past decade to refine the nomenclature of ILCs and highlight the importance of ILCs in tissue homeostasis, morphogenesis, metabolism, repair, and regeneration. Innate lymphoid cells (ILCs), which lack adaptive antigen receptors generated by the recombination of genetic elements, are the innate counterparts of T lymphocytes (Spits et al., 2013Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. Koyasu S. Locksley R.M. McKenzie A.N. Mebius R.E. et al.Innate lymphoid cells--a proposal for uniform nomenclature.Nat. Rev. Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1404) Google Scholar, Eberl et al., 2015Eberl G. Colonna M. Di Santo J.P. McKenzie A.N. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology.Science. 2015; 348: aaa6566Crossref PubMed Scopus (368) Google Scholar, Artis and Spits, 2015Artis D. Spits H. The biology of innate lymphoid cells.Nature. 2015; 517: 293-301Crossref PubMed Scopus (753) Google Scholar). ILC1s, ILC2s, and ILC3s mirror CD4+ T helper (Th)1, Th2, and Th17 cells, respectively, in terms of function, whereas natural killer (NK) cells mirror the functions of CD8+ cytotoxic T cells. ILCs and T cells play key roles in orchestrating the most appropriate immune response to the threat faced by the individual. ILC1s and Th1 cells react to intracellular pathogens, such as viruses, and to tumors; ILC2s and Th2 cells respond to large extracellular parasites and allergens; and ILC3s and Th17 cells combat extracellular microbes, such as bacteria and fungi. Myeloid and non-hematopoietic cells instruct the ILCs and T cells, which belong to the lymphoid lineage, about the type of threat they will confront. The ILCs and T cells react by providing positive and negative feedbacks and through immune regulatory and effector functions. This initial description of a simple phenotypic and functional trichotomy has been greatly enriched and has become much more complex since the discovery of these subsets 10 years ago. This review aims to clarify this complexity and to propose an updated and operational classification and nomenclature for ILCs. ILCs act early in the immune response by reacting promptly to signals, or inducer cytokines, expressed by tissue-resident cells. By contrast, the T cell response takes several days, as these cells must undergo clonal expansion to become operational and develop antigen-specific memory. Nevertheless, several types of T cells are “pre-programmed” and function like innate cells in certain tissues. These cells include invariant NKT cells, mucosa-associated invariant T (MAIT) cells, diverse subsets of γδ T cells and resident memory T (TRM) cells selected and expanded during earlier encounters with antigen (Mueller and Mackay, 2016Mueller S.N. Mackay L.K. Tissue-resident memory T cells: local specialists in immune defence.Nat. Rev. Immunol. 2016; 16: 79-89Crossref PubMed Scopus (356) Google Scholar). A few days after the initiation of an immune reaction, both ILCs and T cells are active, and they cross-regulate each other. ILCs can express major histocompatibility complex (MHC) class II molecules and process antigens, thereby regulating the activity of antigen-specific T cells (Oliphant et al., 2014Oliphant C.J. Hwang Y.Y. Walker J.A. Salimi M. Wong S.H. Brewer J.M. Englezakis A. Barlow J.L. Hams E. Scanlon S.T. 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. 2014; 41: 283-295Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar). In turn, these T cells produce interleukin-2 (IL-2), promoting ILC activities. Both types of cell generate positive-feedback loops that amplify their responses, but they also compete for the same inducer cytokines and survival factors. Thus, these two types of lymphoid cells mirror one another’s activities only partially, thereby ensuring the timely orchestration of the immune response. ILCs begin functioning during fetal development, as lymphoid tissue-inducer cells (LTi cells) (Mebius et al., 1997Mebius R.E. Rennert P. Weissman I.L. Developing lymph nodes collect CD4+CD3- LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells.Immunity. 1997; 7: 493-504Abstract Full Text Full Text PDF PubMed Google Scholar). These cells induce the development of most of the secondary lymphoid organs. They instruct mesenchymal stromal cells to produce the factors required to attract hematopoietic cells to the developing lymphoid structure and retain them there. The interaction between ILCs and the non-hematopoietic microenvironment is an important facet of ILC function maintained from birth into adulthood. It includes the activation of stromal cells for the recruitment, retention, and activation of lymphocytes, and for their regeneration and the activation of defensive and anti-apoptotic programs in epithelial cells. Thus, through their generation early during the formation of the immune system and their prompt reactivity, ILCs play an important role in the crosstalk of lymphoid cells with non-hematopoietic cells and in the spatial organization of immunity. ILCs are clearly the innate counterpart of T cell effector subsets, but research into ILCs has opened up an unprecedented appreciation of the profound involvement of immune cells in tissue homeostasis, whether morphogenesis, metabolism, regeneration, and growth. ILCs are largely tissue-resident cells and are integrated deep into the fabric of tissues, and studies of these cells have revealed ever more intriguing relationships with basic developmental and biological processes. ILCs play a key role in homeostasis, due to the rapidity with which they react and their presence in normal healthy tissues, including the intestine, lung and adipose tissues, in particular. An absence of ILC3s in the intestine can lead to a loss of control over the symbiotic microbiota. In adipose tissues, ILC2s are involved in thermogenesis in the context of a cold shock. ILCs are also involved in tissue tolerance and regeneration in response to tissue damage. In the intestine and thymus, ILC3s mediate tolerance to chemical toxins and irradiation through the activation of epithelial cells, whereas ILC2s produce amphiregulin (AREG), a member of the EGF family, which is involved in epithelial cell regulation. However, these functions can also favor the development of carcinoma during chronic inflammation and injury, and increase the severity of inflammation induced by pathogens. The presence of ILCs in non-lymphoid tissues is ensured by the recruitment of ILC progenitors from the blood, and maintained by the expression of local survival factors, such as IL-7. ILCs have slightly different phenotypes in different tissues, and different local microenvironments may induce ILC progenitors from the same subset to adopt tissue-specific expression patterns. Most ILCs are tissue-resident cells (Gasteiger et al., 2015Gasteiger G. Fan X. Dikiy S. Lee S.Y. Rudensky A.Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.Science. 2015; 350: 981-985Crossref PubMed Scopus (335) Google Scholar), but ILC3s can migrate from the intestinal lamina propria to the draining mesenteric lymph node, and NK cells and inflammatory ILC2s circulate in the bloodstream. We first proposed a common nomenclature for ILCs and ILC subsets in 2013 (Spits et al., 2013Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. Koyasu S. Locksley R.M. McKenzie A.N. Mebius R.E. et al.Innate lymphoid cells--a proposal for uniform nomenclature.Nat. Rev. Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1404) Google Scholar). The use of single-cell RNA sequencing has led to the identification of more than 50 distinct ILC clusters (in t-distributed stochastic neighbor embedding [t-SNE] projection analysis) in different tissues (Gury-BenAri et al., 2016Gury-BenAri M. Thaiss C.A. Serafini N. Winter D.R. Giladi A. Lara-Astiaso D. Levy M. Salame T.M. Weiner A. David E. et al.The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome.Cell. 2016; 166: 1231-1246.e13Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar). We have re-evaluated the original nomenclature, taking into account the identification of ILC developmental lineages, transcriptional networks coordinating ILC effector functions and phenotypes, activation states, and tissue-specific adaptations, and we propose here an updated and comprehensive, but simple and practical, nomenclature for ILCs. We also provide an overview of the newly discovered roles of ILCs in defense, metabolism, repair and interactions with the nervous system. The nomenclature for ILCs proposed in 2013 classified these cells into groups 1, 2, and 3, each of which contained one, two or three subsets. The subsets within each group had the same output, including cytokines in particular, and their development and function were dependent on the same transcription factors. Group 1 ILCs comprised NK cells and ILC1s. These cells are dependent on the T-box transcription factor Tbet for their development and function, and they produce interferon-gamma (IFN-γ). Group 2 contains a single subset, ILC2s, which are dependent on GATA3 and RORα (Wong et al., 2012Wong S.H. Walker J.A. Jolin H.E. Drynan L.F. Hams E. Camelo A. Barlow J.L. Neill D.R. Panova V. Koch U. et al.Transcription factor RORα is critical for nuocyte development.Nat. Immunol. 2012; 13: 229-236Crossref PubMed Scopus (386) Google Scholar), and produce type 2 cytokines, predominantly IL-5 and IL-13. Group 3 ILCs include natural cytotoxicity receptor (NCR)− ILC3s, NCR+ ILC3s, and LTi cells, all of which are dependent on the transcription factor RORγt and can produce IL-17 and/or IL-22. The last decade has provided a wealth of data on the mechanisms of development and the molecules involved in the functions of T helper cell subsets, which has improved our understanding of the development of ILC subsets (Eberl et al., 2015Eberl G. Colonna M. Di Santo J.P. McKenzie A.N. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology.Science. 2015; 348: aaa6566Crossref PubMed Scopus (368) Google Scholar, Artis and Spits, 2015Artis D. Spits H. The biology of innate lymphoid cells.Nature. 2015; 517: 293-301Crossref PubMed Scopus (753) Google Scholar). Within the three initially proposed ILC groups, we now appreciate the existence of distinct subsets based on developmental trajectories. As such, we now propose to classify ILCs into five subsets—NK cells, ILC1s, ILC2s, ILC3s, and LTi cells—based on their development (Figure 1) and function (Figure 2). The ILC nomenclature presented here is approved by the International Union of Immunological Societies (IUIS).Figure 2Immune Function of ILCsShow full captionSome of the most well-known immune function of each ILC subset is shown: NK cells and ILC1s react to intracellular pathogens, such as viruses, and to tumors; ILC2s respond to large extracellular parasites and allergens; ILC3s combat extracellular microbes, such as bacteria and fungi; and LTis are involved in the formation of secondary lymphoid structures. For each ILC subset, effector molecules that can be produced upon activation are indicated.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Some of the most well-known immune function of each ILC subset is shown: NK cells and ILC1s react to intracellular pathogens, such as viruses, and to tumors; ILC2s respond to large extracellular parasites and allergens; ILC3s combat extracellular microbes, such as bacteria and fungi; and LTis are involved in the formation of secondary lymphoid structures. For each ILC subset, effector molecules that can be produced upon activation are indicated. NK cells are dedicated cytotoxic cells that circulate in the bloodstream (Vivier et al., 2011Vivier E. Raulet D.H. Moretta A. Caligiuri M.A. Zitvogel L. Lanier L.L. Yokoyama W.M. Ugolini S. Innate or adaptive immunity? The example of natural killer cells.Science. 2011; 331: 44-49Crossref PubMed Scopus (1456) Google Scholar). They can kill virus-infected normal and tumor cells. In the mouse thymus, conventional NK cells (cNK) coexist with ILC1s that express CD127 (IL-7Rα) and GATA3, unlike cNK cells, produce IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) at much higher levels than cNK cells, and depend on the cytokine IL-7 and the transcription factor GATA3 for their differentiation (Vosshenrich et al., 2006Vosshenrich C.A. García-Ojeda M.E. Samson-Villéger S.I. Pasqualetto V. Enault L. Richard-Le Goff O. Corcuff E. Guy-Grand D. Rocha B. Cumano A. et al.A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127.Nat. Immunol. 2006; 7: 1217-1224Crossref PubMed Scopus (338) Google Scholar). ILC1s are generally non-cytotoxic or weakly cytotoxic and function as a first line of defense against infections with viruses and certain bacteria, such as T. gondii (Klose et al., 2014Klose C.S.N. Flach M. Möhle L. Rogell L. Hoyler T. Ebert K. Fabiunke C. Pfeifer D. Sexl V. Fonseca-Pereira D. et al.Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages.Cell. 2014; 157: 340-356Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar) or C. difficile (Abt et al., 2015Abt M.C. Lewis B.B. Caballero S. Xiong H. Carter R.A. Sušac B. Ling L. Leiner I. Pamer E.G. Innate immune defenses mediated by two ILC subsets are critical for protection against acute clostridium difficile infection.Cell Host Microbe. 2015; 18: 27-37Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). NK cells and ILC1s have several features in common. Both these cell types produce IFN-γ as their principal cytokine output and require Tbet for this function. However, they have different developmental paths (Figure 1). In both humans and in mice, NK cells develop from a common innate lymphoid progenitor (CILP) via an NK cell precursor (NKP), whereas ILC1s develop from CILPs via an innate lymphoid cell precursor (ILCP) (Constantinides et al., 2014Constantinides M.G. McDonald B.D. Verhoef P.A. Bendelac A. A committed precursor to innate lymphoid cells.Nature. 2014; 508: 397-401Crossref PubMed Scopus (438) Google Scholar, Klose et al., 2014Klose C.S.N. Flach M. Möhle L. Rogell L. Hoyler T. Ebert K. Fabiunke C. Pfeifer D. Sexl V. Fonseca-Pereira D. et al.Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages.Cell. 2014; 157: 340-356Abstract Full Text Full Text PDF PubMed Scopus (598) Google Scholar, Lim et al., 2017Lim A.I. Li Y. Lopez-Lastra S. Stadhouders R. Paul F. Casrouge A. Serafini N. Puel A. Bustamante J. Surace L. et al.Systemic human ILC precursors provide a substrate for tissue ILC differentiation.Cell. 2017; 168: 1086-1100.e10Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, Renoux et al., 2015Renoux V.M. Zriwil A. Peitzsch C. Michaëlsson J. Friberg D. Soneji S. Sitnicka E. Identification of a human natural killer cell lineage-restricted progenitor in fetal and adult tissues.Immunity. 2015; 43: 394-407Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, Scoville et al., 2016Scoville S.D. Mundy-Bosse B.L. Zhang M.H. Chen L. Zhang X. Keller K.A. Hughes T. Chen L. Cheng S. Bergin S.M. et al.A progenitor cell expressing transcription factor RORγt generates all human innate lymphoid cell subsets.Immunity. 2016; 44: 1140-1150Abstract Full Text Full Text PDF PubMed Google Scholar). NK cells and ILC1s are functionally different, as NK cells are dedicated cytotoxic cells strongly expressing perforin, whereas ILC1s have low levels of perforin expression. However, regardless of these developmental and functional differences, the phenotypic characterization of ILC1s is often problematic. ILC1s preferentially express CD49a and TRAIL in both humans and mice, but the specificity of these markers is often lost upon cell activation and is tissue-dependent. ILC1s have some phenotypic markers in common with NK cells and ILC3s, in at least some organs. These markers include NK1.1 in mice, and NCRs, such as NKp44 in humans, and NKp46 in both humans and mice (Table 1). In humans, ILC1s express CD127 whereas highly cytotoxic CD16+CD56+ NK cells do not express this marker. However, CD127 may not be an absolute ILC marker in humans because a majority of CD16−CD56bright NK cells in peripheral blood do express CD127. CD200R expression has been shown to distinguish ILC1s from NK cells in mice (Weizman et al., 2017Weizman O.E. Adams N.M. Schuster I.S. Krishna C. Pritykin Y. Lau C. Degli-Esposti M.A. Leslie C.S. Sun J.C. O’Sullivan T.E. ILC1 confer early host protection at initial sites of viral infection.Cell. 2017; 171: 795-808.e12Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). Another marker of human NK cells is NKp80, which is not expressed on ILC1s (Freud et al., 2016Freud A.G. Keller K.A. Scoville S.D. Mundy-Bosse B.L. Cheng S. Youssef Y. Hughes T. Zhang X. Mo X. Porcu P. et al.NKp80 defines a critical step during human natural killer cell development.Cell Rep. 2016; 16: 379-391Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). ILC1s are tissue-resident cells, whereas NK cells circulate in the bloodstream (Peng et al., 2013Peng H. Jiang X. Chen Y. Sojka D.K. Wei H. Gao X. Sun R. Yokoyama W.M. Tian Z. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation.J. Clin. Invest. 2013; 123: 1444-1456Crossref PubMed Scopus (298) Google Scholar, Gasteiger et al., 2015Gasteiger G. Fan X. Dikiy S. Lee S.Y. Rudensky A.Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.Science. 2015; 350: 981-985Crossref PubMed Scopus (335) Google Scholar). In mice, ILC1s are first detected before birth, whereas NK cells emerge two to three weeks after birth (Diefenbach et al., 2014Diefenbach A. Colonna M. Koyasu S. Development, differentiation, and diversity of innate lymphoid cells.Immunity. 2014; 41: 354-365Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar). There are also differences in the production of and dependence on transcription factors. In mice, ILC1s are strictly dependent on Tbet, whereas NK cells are present in Tbet-deficient hosts (Daussy et al., 2014Daussy C. Faure F. Mayol K. Viel S. Gasteiger G. Charrier E. Bienvenu J. Henry T. Debien E. Hasan U.A. et al.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. 2014; 211: 563-577Crossref PubMed Scopus (287) Google Scholar). In addition, NK cells require the T-box factor Eomes, whereas ILC1s can develop in the absence of this transcription factor. Eomes expression is, therefore, often used as a marker for NK cells, although it can be expressed on a proportion of ILC1s.Table 1Main Phenotypic Markers of the Different Subsets of Murine and Human ILCsMouseHumanNKILC1ILC2LTiNKp46− ILC3NKp46+ ILC3NKILC1ILC2LTiNKp44− ILC3NKp44+ ILC3Cell-surface moleculesCD45+++int++CD45++++int++CD127 (IL-7Ra)aNot expressed by NK cells of liver, intestine, skin, uterus, salivary gland, bone marrow, or lymph nodes. Expressed by NK cells in the thymus and in some spleen populations.bExpressed by the majority of ILC1, except for liver populations and intraepithelial gut ILC1.+++WWCD127 (IL-7Ra)–/+eExpressed by the majority of ILC1, except for tonsil and intraepithelial ILC1.++++CD161 (NK1.1)++––––/+CD161 (NK1.1)+/−+++/−++ST2 (IL-33R)–nd+/−ndndndST2 (IL-33R)+/−–+/−ndnd–CD278 (ICOS)Wnd++ndWWCD278 (ICOS)–nd+ndnd+IL-17Rβ (IL25R)–nd+–––IL-17Rβ (IL25R)––+–nd–CD294 (CRTH2)–nd+ndndndCD294 (CRTH2)––+–––KLRG1++–+–––KLRG1+–+–––CD117 (c-kit)-+/−+/−++WWCD117 (c-kit)–/W–+/−+++CD69cExpressed by NK cells of the intestine, uterus, and thymus, but not the spleen and liver.+ndndndndCD69W+/−ndndndndCD254 (RANKL)ndndnd+++CD254 (RANKL)–ndnd+++CD196 (CCR6)–nd–++/−–CD196 (CCR6)–+/−+/−++/−+/−CD335 (NKp46)++–––+CD335 (NKp46)+–––-/WW/+CD25 (IL-2Rα)dExpressed by activated cells.–/W++/−+/−+/−CD25 (IL-2Rα)+/−W+W+/−–/WMHC-II––+++–MHC-II+/−nd+/−ndnd+/−IL23R––nd+++IL23R+/−+/−–/W+++IL1Rβ–+nd+++IL1R+/−+W+++CD122++W–––CD122+ndnd–/WWWCD314 (NKG2D)+nd–––+CD314 (NKG2D)+ndnd–-W–/WLy49+/−+/−––––KIR+/−–––––CD94+/−nd+/−nd–+/−CD94+/−–––––Perforin+W––––Perforin+–––––CD253 (TRAIL)–+ndndndndIL12Rβ++–––+/−Sca-1 (Ly6a)dExpressed by activated cells.++–nd+CD194 (CCR4)nd+/−+ndndndCD49d (integrin α4β7)ndnd–nd++CD56+–––/W+/−+/−CD49a (integrin α1β1)aNot expressed by NK cells of liver, intestine, skin, uterus, salivary gland, bone marrow, or lymph nodes. Expressed by NK cells in the thymus and in some spleen populations.+ndndndndCD183 (CXCR3)nd+ndndndndCD90 (Thy1)+/−+++++CD337 (NKp30)++++/−+/−+/−CD160fNot expressed by NK cells of the spleen, liver, uterus, or blood. Expressed by NK cells in the gut.+ndndndndCD336 (NKp44)dExpressed by activated cells.––––+CD103gNot expressed by liver or spleen NK cells. Expressed by NK cells in the blood.–ndndndndCD16+/−–––––CD200R–+ndndndndNKp80+–ndndndndTranscription factorsTbet++––+/−+Tbet++––––Eomes++/–––––Eomes++/–––––RORγt–––+++RORγt––/W–/W+++GATA3–/W–/W+–/W–/W–/WGATA3–/W–/W+–/W–/W–/WAhR–ndnd+++AhR–/WW++++RORαndnd+ndndndThe expression of certain markers varies according to the organs. int, intermediate expression; W, weak expression; nd, not determined. “+/−” means that expression is detected in some, but not all, cells.a Not expressed by NK cells of liver, intestine, skin, uterus, salivary gland, bone marrow, or lymph nodes. Expressed by NK cells in the thymus and in some spleen populations.b Expressed by the majority of ILC1, except for liver populations and intraepithelial gut ILC1.c Expressed by NK cells of the intestine, uterus, and thymus, but not the spleen and liver.d Expressed by activated cells.e Expressed by the majority of ILC1, except for tonsil and intraepithelial ILC1.f Not expressed by NK cells of the spleen, liver, uterus, or blood. Expressed by NK cells in the gut.g Not expressed by liver or spleen NK cells. Expressed by NK cells in the blood. Open table in a new tab The expression of certain markers varies according to the organs. int, intermediate expression; W, weak expression; nd, not determined. “+/−” means that expression is detected in some, but not all, cells. ILC2s are defined by their capacity to produce the type 2 cytokines IL-4, IL-5, and IL-13 (Moro et al., 2010Moro K. Yamada T. Tanabe M. Takeuchi T. Ikawa T. Kawamoto H. Furusawa J. Ohtani M. Fujii H. Koyasu S. 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Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs.Science. 2015; 350: 981-985Crossref PubMed Scopus (335) Google Scholar, Moro et al., 2016Moro K. Kabata H. Tanabe M. Koga S. Takeno N. Mochizuki M. Fukunaga K. Asano K. Betsuyaku T. Koyasu S. Interferon and IL-27 antagonize the function of group 2 innate lymphoid cell function and type 2 innate immune responses.Nat. Immunol. 2016; 17: 76-86Crossref PubMed Scopus (0) Google Scholar). They respond to the cytokines IL-25, TSLP, and IL-33. ILC2s are involved in the innate immune response to parasites, such as the helminth Nippostrongulus brasiliensis. After resolving the infection, ILC2s help to repair damaged tissues by producing AREG (Monticelli et al., 2011Monticelli L.A. Sonnenberg G.F. Abt M.C. Alenghat T. Ziegler C.G. Doering T.A. Angelosanto J.M. Laidlaw B.J. Yang C.Y. 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