The 3 major types of innate and adaptive cell-mediated effector immunity

The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet+ IFN-γ–producing group 1 ILCs (ILC1 and natural killer cells), CD8+ cytotoxic T cells (TC1), and CD4+ TH1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3+ ILC2s, TC2 cells, and TH2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid–related orphan receptor γt+ ILC3s, TC17 cells, and TH17 cells producing IL-17, IL-22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases. The immune system has tailored its effector functions to optimally respond to distinct species of microbes. Based on emerging knowledge on the different effector T-cell and innate lymphoid cell (ILC) lineages, it is clear that the innate and adaptive immune systems converge into 3 major kinds of cell-mediated effector immunity, which we propose to categorize as type 1, type 2, and type 3. Type 1 immunity consists of T-bet+ IFN-γ–producing group 1 ILCs (ILC1 and natural killer cells), CD8+ cytotoxic T cells (TC1), and CD4+ TH1 cells, which protect against intracellular microbes through activation of mononuclear phagocytes. Type 2 immunity consists of GATA-3+ ILC2s, TC2 cells, and TH2 cells producing IL-4, IL-5, and IL-13, which induce mast cell, basophil, and eosinophil activation, as well as IgE antibody production, thus protecting against helminthes and venoms. Type 3 immunity is mediated by retinoic acid–related orphan receptor γt+ ILC3s, TC17 cells, and TH17 cells producing IL-17, IL-22, or both, which activate mononuclear phagocytes but also recruit neutrophils and induce epithelial antimicrobial responses, thus protecting against extracellular bacteria and fungi. On the other hand, type 1 and 3 immunity mediate autoimmune diseases, whereas type 2 responses can cause allergic diseases. In 1986, Mosmann et al1Mosmann T.R. Cherwinski H. Bond M.W. Giedlin M.A. Coffman R.L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.J Immunol. 1986; 175: 5-14Google Scholar demonstrated that murine CD4+ TH cells can be classified into 2 major functionally different subsets on the basis of the different cytokines they produce (ie, TH1 and TH2). The first clear evidence for the existence of TH1 and TH2 cells in human subjects was provided only 5 years later.2Romagnani S. Human TH1 and TH2 subsets: doubt no more.Immunol Today. 1991; 12: 256-257Abstract Full Text PDF PubMed Scopus (1008) Google Scholar As known, TH1 cells produce IFN-γ and lymphotoxin (LT) α, whereas TH2 cells produce IL-4, IL-5, and IL-13.3Romagnani S. Lymphokine production by human T cells in human disease states.Annu Rev Immunol. 1994; 12: 227-257Crossref PubMed Google Scholar Subsequently, a similar dichotomy within the CD8+ cytotoxic T (TC) cell population was discovered in both mice and human subjects, and the 2 subsets were named TC1 and TC2, respectively.4Mosmann T.R. Sad S. Krishnan L. Wegmann T.G. Guilbert L.J. Belosevic M. Differentiation of subsets of CD4+ and CD8+ T cells.Ciba Found Symp. 1995; 195: 42-50PubMed Google Scholar In 2005, a third subset of murine CD4+ TH cells was identified and named TH17 cells because of the unique ability of these cells to produce IL-17.5Harrington L.E. Hatton P.R. Mangan H. Turner T.L. Murphy T.L. Murphy K.M. et al.Interleukin17-producing CD4+ effector T cells develop via lineage distinct from the T helper type 1 and 2 lineages.Nat Immunol. 2005; 6: 1123-1132Crossref PubMed Scopus (3777) Google Scholar Two years later, TH17 cells were found to exist in human subjects.6Acosta-Rodriguez E.V. Rivino L. Geginat J. Jarrossay D. Gattorno M. Lanzavecchia A. et al.Surface phenotype and antigen specificity of human interleukin 17-producing T helper memory cells.Nat Immunol. 2007; 8: 639-646Crossref PubMed Scopus (1425) Google Scholar, 7Annunziato F. Cosmi L. Santarlasci V. Maggi L. Liotta F. Mazzinghi B. et al.Phenotypic and functional features of human Th17 cells.J Exp Med. 2007; 204: 1849-1861Crossref PubMed Scopus (1497) Google Scholar Likewise, CD8+ T cells producing IL-17 were identified and named TC17 cells.8Kondo T. Takata H. Matsuki F. Takiguchi M. Cutting edge: phenotypic characterization and differentiation of human CD8+ T cells producing IL-17.J Immunol. 2009; 182: 1794-1798Crossref PubMed Scopus (146) Google Scholar In the last few years, the existence of innate lymphoid cells (ILCs), which differ from classic T cells because they lack the T-cell receptor, has been reported both in mice and human subjects.9Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Ebert G. et al.Innate lymphoid cells—a proposal for uniform nomenclature.Nat Rev Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1730) Google Scholar Because of their similarity to CD4+ and CD8+ T cells, it was recently proposed that ILCs can be classified into cytotoxic ILCs, namely natural killer (NK) cells, and helper ILCs, which, like CD4+ TH cells, can be separated into the 3 main lineages ILC1s, ILC2s, and ILC3s, according to their ability to produce type 1, type 2, or type 17 cytokines, respectively.9Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Ebert G. et al.Innate lymphoid cells—a proposal for uniform nomenclature.Nat Rev Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1730) Google Scholar, 10Klose C.S. Flach M. Mohle L. Rogell L. Hoyler T. Ebert K. 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 (777) Google Scholar ILC3s are also present before birth in which case they are named lymphoid tissue inducer cells because of their crucial role in promoting lymph node and Peyer patch formation during fetal development.9Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Ebert G. et al.Innate lymphoid cells—a proposal for uniform nomenclature.Nat Rev Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1730) Google Scholar Although both T cells and ILCs originate from a common lymphoid progenitor, differentiation of naive CD8+ and CD4+ T cells from the T-cell precursor occurs in the thymus, and the different developmental steps have been elucidated clearly. Conversely, the location and stages of ILC differentiation are only beginning to be clarified. Helper-like ILCs and cytotoxic NK cells likely differentiate from a putative common innate lymphoid precursor, from which the “common helper-like ILC progenitor,” which was recently identified in the mouse,10Klose C.S. Flach M. Mohle L. Rogell L. Hoyler T. Ebert K. 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 (777) Google Scholar and the NK cell progenitor (NKp) might originate. Taking into account this ontogenetic pathway, as well as the different effector functions and pathophysiologic effects, it is now possible to distinguish 3 major types of innate and adaptive cell-mediated effector immunity, which we propose to define as type 1, type 2, and type 3, respectively (Fig 1). These different types of cell-mediated immunity exist to ensure a tailored and maximally protective effect against the great variety of pathogenic microorganisms present in the environment. However, because of innate or acquired deficiencies, as well as abnormal or exaggerated responses, they can also generate different types of immune-mediated disorders. In this review we will discuss the 3 types of immunity, with particular focus on the main features of human cells and their respective role in protection and immunopathology. Type 1 cell-mediated effector immunity provides an effective response against intracellular microbes, such as bacteria, protozoa, and some viruses, and it comprises T-bet+ IFN-γ–producing helper cells (ie, CD4+ TH1 cells and ILC1s), as well as T-bet+ eomesodermin (Eomes)+ cytotoxic lymphocytes, namely CD8+ T cells and NK cells. The main features of the innate and adaptive cells involved in type 1 immunity are depicted in Fig 2. As mentioned above, in both mice and human subjects, TH1 cells make IFN-γ and LT-α as their signature cytokines1Mosmann T.R. Cherwinski H. Bond M.W. Giedlin M.A. Coffman R.L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.J Immunol. 1986; 175: 5-14Google Scholar, 2Romagnani S. Human TH1 and TH2 subsets: doubt no more.Immunol Today. 1991; 12: 256-257Abstract Full Text PDF PubMed Scopus (1008) Google Scholar but can also produce TNF and IL-2 and mediate mononuclear phagocyte (MP) activation. Moreover, TH1 cells are able to help the production by B lymphocytes of antibodies of the IgG2a isotype in mice1Mosmann T.R. Cherwinski H. Bond M.W. Giedlin M.A. Coffman R.L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.J Immunol. 1986; 175: 5-14Google Scholar and of IgM, IgG, and IgA, but not IgE, in human subjects.3Romagnani S. Lymphokine production by human T cells in human disease states.Annu Rev Immunol. 1994; 12: 227-257Crossref PubMed Google Scholar The environmental cytokine mainly responsible for human TH1 cell differentiation is IL-12,11Manetti R. Parronchi P. Giudizi M.G. Piccinni M.P. Maggi E. Trinchieri G. et al.Natural killer cell stimulatory factor (interleukin 12 IL-12) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells.J Exp Med. 1993; 177: 1199-1204Crossref PubMed Scopus (1640) Google Scholar which is produced by dendritic cells (DCs) in response to the interaction of pattern recognition receptors with bacterial or viral conserved structures. IFN-γ also contributes to TH1 cell differentiation, whereas IFN-α is involved in human subjects but not in mice.12Farrar J.D. Asnagli H. Murphy K.M. T helper subset development: roles of instruction, selection, and transcription.J Clin Invest. 2002; 109: 431-435Crossref PubMed Google Scholar More recently, 2 other cytokines, IL-23 and IL-27, have been found to have a TH1-polarizing activity.13Brombacher F. Kastelein R.A. Alber G. Novel IL-12 family members shed light on the orchestration of Th1 responses.Trends Immunol. 2003; 24: 207-212Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar Activation of signal transducer and activator of transcription (STAT) 1 by IFN-γ and of STAT4 by IL-12 is critical for the induction of T-bet, which is considered the hallmark transcription factor for TH1 cells.12Farrar J.D. Asnagli H. Murphy K.M. T helper subset development: roles of instruction, selection, and transcription.J Clin Invest. 2002; 109: 431-435Crossref PubMed Google Scholar In addition to the production of IFN-γ and expression of T-bet, TH1 cells are also characterized by the expression of chemokine receptors, which allow their recruitment to inflammatory sites. The main chemokine receptors of TH1 cells are CXCR3A and CCR5.14Bonecchi R. Bianchi G. Bordignon P.P. D'Ambrosio D. Lang R. 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Wanke K. et al.Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-γ and IL-4.J Allergy Clin Immunol. 2012; 130: 1087-1096Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar as well as by increasing the apoptosis of keratinocytes in the skin.16Rebane A. Zimmermann M. Aab A. Baurecht H. Koreck A. Karelson M. et al.Mechanisms of IFN-γ-induced apoptosis of human keratinocytes in patients with atopic dermatitis.J Allergy Clin Immunol. 2012; 129: 1297-1306Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar On the other hand, it is known that both keratinocytes and epithelial cells produce CXCL9, CXCL10, and CXCL11 in response to IFN-γ, thus favoring recruitment of TH1 cells.17Klunker S. Trautmann A. Akdis M. Verhagen J. Schmid-Grendelmeier P. Blaser K. et al.A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant for T cell chemotaxis toward epidermis in atopic dermatitis.J Immunol. 2003; 171: 1078-1084Crossref PubMed Scopus (108) Google Scholar CD8+ T cells generally produce IFN-γ, TNF and LT-α. However, after the discovery of TH1 and TH2 cells, the existence of CD8+ T cells able to produce IL-4 and IL-5 instead of IFN-γ was reported, and therefore IFN-γ–producing CD8+ T cells were renamed TC1 cells.4Mosmann T.R. Sad S. Krishnan L. Wegmann T.G. Guilbert L.J. Belosevic M. Differentiation of subsets of CD4+ and CD8+ T cells.Ciba Found Symp. 1995; 195: 42-50PubMed Google Scholar Like CD4+ TH1 differentiation, IFN-γ and IL-12 promote differentiation toward TC1 cells.18Carter L.L. Murphy K.M. Lineage-specific requirement for signal transducer and activator of transcription (Stat)4 in interferon gamma production from CD4 (+) versus CD8(+) T cells.J Exp Med. 1999; 189: 1355-1360Crossref PubMed Scopus (147) Google Scholar However, in response to antigen, TC1 cells can be induced to produce IFN-γ independently of IL-12 and STAT4 activation.19Glimcher L.H. Townsend M.J. Sullivan B.M. Lord G.M. Recent developments in the transcriptional regulation of cytolytic effector cells.Nat Rev Immunol. 2004; 4: 900-911Crossref PubMed Scopus (244) Google Scholar T-bet activation in TC1 cells is required for both IFN-γ production and cytolytic potential. In the same cells both these activities are also under the control of another T-box transcription factor, Eomes.19Glimcher L.H. Townsend M.J. Sullivan B.M. Lord G.M. Recent developments in the transcriptional regulation of cytolytic effector cells.Nat Rev Immunol. 2004; 4: 900-911Crossref PubMed Scopus (244) Google Scholar As has been shown for TH1 cells, CCR5 and CXCR3 are the main chemokine receptors for TC1 cells.20Larrubia J.R. Calvino M. Benito S. Sanz-de-Villalobos E. Perna C. Pèrez-Hornedo J. et al.The role of CCR5/CXCR3 expressing CD8+ cells in liver damage and viral control during persistent hepatitis C virus infection.J Hepatol. 2007; 47: 632-641Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Group 1 ILCs were defined to include ILCs expressing T-bet and producing IFN-γ and originally were composed of only NK cells. NK cells are NKp46+ cytotoxic lymphocytes producing IFN-γ in response to cytokines and/or activating receptor engagement and depend on IL-15 and E4bp4 (a member of the bZIP family of DNA-binding proteins) for their development. NK cells have been mostly characterized in human peripheral blood (PB), where they represent around 5% to 15% of circulating lymphocytes, and in mouse spleens, where they coexpress the transcription factors T-bet and Eomes, which is similar to CD8+ T cells.21Sun J.C. Lanier L.L. NK cell development, homeostasis and function: parallels with CD8+ T cells.Nat Rev Immunol. 2011; 11: 645-657Crossref PubMed Scopus (470) Google Scholar However, it was recently shown that among NKp46+ cells resident in various tissues, a large heterogeneity can be appreciated concerning phenotype, expression of master transcription factors, and developmental dependence, and in some reports these cells have been designated as distinct lineages from NK cells termed ILC1s.10Klose C.S. Flach M. Mohle L. Rogell L. Hoyler T. Ebert K. 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 (777) Google Scholar, 22Bernink J.H. Peters C.P. Munneke M. te Velde A.A. Meijer S.L. Weijer K. et al.Human type 1 innate lymphoid cells accumulate in inflamed mucosa tissues.Nat Immunol. 2013; 14: 221-229Crossref PubMed Scopus (716) Google Scholar, 23Fuchs A. Vermi W. Lee J.S. Lonardi S. Gilfilan S. Newberrry R.D. et al.Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells.Immunity. 2013; 38: 769-781Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar, 24Sojka D.K. Plougastel-Douglas B. Yang L. Pak-Wittel M.A. Artyomov M.N. Ivanova Y. et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells.Elife. 2014; 3: e01659Crossref Scopus (385) Google Scholar, 25Tanriver Y. Diefenbach A. Transcription factors controlling development and function of innate lymphoid cells.Int Immunol. 2014; 26: 119-128Crossref PubMed Scopus (33) Google Scholar ILC1s appear to be functionally characterized by the ability to produce IFN-γ, TNF, GM-CSF, and even IL-2 in response to cytokine stimulation but have low or no cytotoxic ability.10Klose C.S. Flach M. Mohle L. Rogell L. Hoyler T. Ebert K. 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 (777) Google Scholar, 22Bernink J.H. Peters C.P. Munneke M. te Velde A.A. Meijer S.L. Weijer K. et al.Human type 1 innate lymphoid cells accumulate in inflamed mucosa tissues.Nat Immunol. 2013; 14: 221-229Crossref PubMed Scopus (716) Google Scholar, 23Fuchs A. Vermi W. Lee J.S. Lonardi S. Gilfilan S. Newberrry R.D. et al.Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells.Immunity. 2013; 38: 769-781Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar, 24Sojka D.K. Plougastel-Douglas B. Yang L. Pak-Wittel M.A. Artyomov M.N. Ivanova Y. et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells.Elife. 2014; 3: e01659Crossref Scopus (385) Google Scholar However, in some cases cells described as ILC1-like populations rather represent retinoic acid–related orphan receptor (ROR) γt (RORC)+ ILC3s, which, because of their plasticity, have lost the expression of RORγt while acquiring many features of other group 1 ILC cell subsets.22Bernink J.H. Peters C.P. Munneke M. te Velde A.A. Meijer S.L. Weijer K. et al.Human type 1 innate lymphoid cells accumulate in inflamed mucosa tissues.Nat Immunol. 2013; 14: 221-229Crossref PubMed Scopus (716) Google Scholar, 25Tanriver Y. Diefenbach A. Transcription factors controlling development and function of innate lymphoid cells.Int Immunol. 2014; 26: 119-128Crossref PubMed Scopus (33) Google Scholar Interestingly, a mouse α4β7+ progenitor has been recently identified, giving rise to NKp46+T-bet+Eomes− ILC1s (as well as ILC2s and ILC3s) but not to NKp46+T-bet+Eomes+ NK cells.10Klose C.S. Flach M. Mohle L. Rogell L. Hoyler T. Ebert K. 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 (777) Google Scholar Based on all these observations, it was thus proposed that NKp46+ IL-7 receptor (IL-7R)+ T-bet+Eomes− ILC1s (depending on T-bet but not on Eomes or RORγt for their development) could correspond to IFN-γ–producing helper ILCs. Conversely, cytotoxic T-bet+Eomes+ NK cells (depending on Eomes but not on RORγt for their development) might represent a distinct lineage, acting as the innate counterpart of CD8+ T cells.10Klose C.S. Flach M. Mohle L. Rogell L. Hoyler T. Ebert K. 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 (777) Google Scholar However, following these criteria, not all the NKp46+ cells described to date in different tissues can be categorized as NK cells or ILC1s.23Fuchs A. Vermi W. Lee J.S. Lonardi S. Gilfilan S. Newberrry R.D. et al.Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells.Immunity. 2013; 38: 769-781Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar, 24Sojka D.K. Plougastel-Douglas B. Yang L. Pak-Wittel M.A. Artyomov M.N. Ivanova Y. et al.Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells.Elife. 2014; 3: e01659Crossref Scopus (385) Google Scholar Therefore further characterization of the large heterogeneity displayed by NKp46+ cells in different tissues and understanding of their developmental requirements and specific functions will enable us to have more insight to better dissect group 1 ILCs. Markers expressed by murine splenic or human PB NK cells versus ILC1s are shown in Table I.9Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Ebert G. et al.Innate lymphoid cells—a proposal for uniform nomenclature.Nat Rev Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1730) Google Scholar, 10Klose C.S. Flach M. Mohle L. Rogell L. Hoyler T. 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Grogan J.L. et al.Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural-killer cells.Nat Immunol. 2009; 10: 66-74Crossref PubMed Scopus (537) Google Scholar Because of their large heterogeneity and the still poor characterization of ILC1s from different tissues, for simplicity, only markers of murine10Klose C.S. Flach M. Mohle L. Rogell L. Hoyler T. Ebert K. 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 (777) Google Scholar and human22Bernink J.H. Peters C.P. Munneke M. te Velde A.A. Meijer S.L. Weijer K. et al.Human type 1 innate lymphoid cells accumulate in inflamed mucosa tissues.Nat Immunol. 2013; 14: 221-229Crossref PubMed Scopus (716) Google Scholar ILC1s identified in the gut lamina propria have been described.Table IMain features of murine and human ILCsMurineHumanNK cells9Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Ebert G. et al.Innate lymphoid cells—a proposal for uniform nomenclature.Nat Rev Immunol. 2013; 13: 145-149Crossref PubMed Scopus (1730) Google Scholar, 21Sun J.C. Lanier L.L. NK cell development, homeostasis and function: parallels with CD8+ T cells.Nat Rev Immunol. 2011; 11: 645-657Crossref PubMed Scopus (470) Google Scholar, 26Killig M. Glatzer T. Romagnani C. Recognition strategies of group 3 innate lymphoid cells.Front Immunol. 2014; 5: 142Crossref PubMed Scopus (52) Google ScholarILC1s10Klose C.S. Flach M. Mohle L. Rogell L. Hoyler T. Ebert K. 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 (777) Google ScholarILC2s25Tanriver Y. Diefenbach A. Transcription factors controlling development and function of innate lymphoid cells.Int Immunol. 2014; 26: 119-128Crossref PubMed Scopus (33) Google Scholar, 26Killig M. 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