• 1
    Spits, H.andCupedo, T., Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 2012. 30: 647675.
  • 2
    Spits, H. and Di Santo, J. P., The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat. Immunol. 12: 2127.
  • 3
    Scandella, E., Bolinger, B., Lattmann, E., Miller, S., Favre, S., Littman, D. R., Finke, D., Luther, S. A., Junt, T. and Ludewig, B., Restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the T cell zone. Nat. Immunol. 2008. 9: 667675.
  • 4
    Monticelli, L. A., Sonnenberg, G. F., Abt, M. C., Alenghat, T., Ziegler, C. G., Doering, T. A., Angelosanto, J. M., et al., Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 2011. 12: 10451054.
  • 5
    Eberl, G., Marmon, S., Sunshine, M. J., Rennert, P. D., Choi, Y. and Littman, D. R., An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 2004. 5: 6473.
  • 6
    Wong, S. H., Walker, J. A., Jolin, H. E., Drynan, L. F., Hams, E., Camelo, A., Barlow, J. L., et al., Transcription factor RORalpha is critical for nuocyte development. Nat. Immunol. 2012. 13: 229236.
  • 7
    Kee, B. L., E and ID proteins branch out. Nat. Rev. Immunol. 2009. 9: 175184.
  • 8
    Barndt, R. J., Dai, M. and Zhuang, Y., Functions of E2A-HEB heterodimers in T-cell development revealed by a dominant negative mutation of HEB. Mol. Cell Biol. 2000. 20: 66776685.
  • 9
    Schotte, R., Dontje, W., Nagasawa, M., Yasuda, Y., Bakker, A. Q., Spits, H. and Blom, B., Synergy between IL-15 and Id2 promotes the expansion of human NK progenitor cells, which can be counteracted by the E protein HEB required to drive T cell development. J. Immunol. 2010. 184: 66706679.
  • 10
    Cisse, B., Caton, M. L., Lehner, M., Maeda, T., Scheu, S., Locksley, R., Holmberg, D., et al., Transcription factor E2–2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 2008. 135: 3748.
  • 11
    Nagasawa, M., Schmidlin, H., Hazekamp, M. G., Schotte, R. and Blom, B., Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix-loop-helix factor E2–2 and the Ets factor Spi-B. Eur. J. Immunol. 2008. 38: 23892400.
  • 12
    Boos, M. D., Yokota, Y., Eberl, G. and Kee, B. L., Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J. Exp. Med. 2007. 204: 11191130.
  • 13
    Yokota, Y., Mansouri, A., Mori, S., Sugawara, S., Adachi, S., Nishikawa, S. and Gruss, P., Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 1999. 397: 702706.
  • 14
    Satoh-Takayama, N., Lesjean-Pottier, S., Vieira, P., Sawa, S., Eberl, G., Vosshenrich, C. A. and Di Santo, J. P., IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46 +cell subsets from Id2-dependent precursors. J. Exp. Med. 2010. 207: 273280.
  • 15
    Moro, K., Yamada, T., Tanabe, M., Takeuchi, T., Ikawa, T., Kawamoto, H., Furusawa, J., et al., Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature 2009. 463: 540544.
  • 16
    Heemskerk, M. H., Blom, B., Nolan, G., Stegmann, A. P., Bakker, A. Q., Weijer, K., Res, P. C. and Spits, H., Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3. J. Exp. Med. 1997. 186: 15971602.
  • 17
    Jaleco, A. C., Stegmann, A. P., Heemskerk, M. H., Couwenberg, F., Bakker, A. Q., Weijer, K. and Spits, H., Genetic modification of human B-cell development: B-cell development is inhibited by the dominant negative helix loop helix factor Id3. Blood 1999. 94: 26372646.
  • 18
    Spits, H., Couwenberg, F., Bakker, A. Q., Weijer, K. and Uittenbogaart, C. H., Id2 and Id3 inhibit development of CD34(+) stem cells into predendritic cell (pre-DC)2 but not into pre-DC1. Evidence for a lymphoid origin of pre-DC2. J. Exp. Med. 2000. 192: 17751784.
  • 19
    Carotta, S., Pang, S. H., Nutt, S. L. and Belz, G. T., Identification of the earliest NK-cell precursor in the mouse BM. Blood 2011. 117: 54495452.
  • 20
    Cherrier, M., Sawa, S. and Eberl, G., Notch, Id2, and RORgammat sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J. Exp. Med. 2012.
  • 21
    Beck, K., Peak, M. M., Ota, T., Nemazee, D. and Murre, C., Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci. J. Exp. Med. 2009. 206: 22712284.
  • 22
    Aliahmad, P. and Kaye, J., Development of all CD4 T lineages requires nuclear factor TOX. J. Exp. Med. 2008. 205: 245256.
  • 23
    Aliahmad, P., de la Torre, B. and Kaye, J., Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nat. Immunol. 2010. 11: 945952.
  • 24
    Aliahmad, P., Seksenyan, A. and Kaye, J., The many roles of TOX in the immune system. Curr. Opin. Immunol. 2012. 24: 173177.
  • 25
    Cupedo, T., Crellin, N. K., Papazian, N., Rombouts, E. J., Weijer, K., Grogan, J. L., Fibbe, W. E., et al., Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat. Immunol. 2009. 10: 6674.
  • 26
    van de Pavert, S. A. and Mebius, R. E., New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 2010. 10: 664674.
  • 27
    Tsuji, M., Suzuki, K., Kitamura, H., Maruya, M., Kinoshita, K., Ivanov, II, Itoh, K., et al., Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 2008. 29: 261271.
  • 28
    Zenewicz, L. A., Yancopoulos, G. D., Valenzuela, D. M., Murphy, A. J., Stevens, S. and Flavell, R. A., Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 2008. 29: 947957.
  • 29
    Takatori, H., Kanno, Y., Watford, W. T., Tato, C. M., Weiss, G., Ivanov, II, Littman, D. R. and O'Shea, J. J., Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 2009. 206: 3541.
  • 30
    Satoh-Takayama, N., Vosshenrich, C. A., Lesjean-Pottier, S., Sawa, S., Lochner, M., Rattis, F., Mention, J. J., et al., Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 2008. 29: 958970.
  • 31
    Luci, C., Reynders, A., Ivanov, II, Cognet, C., Chiche, L., Chasson, L., Hardwigsen, J., et al., Influence of the transcription factor RORgammat on the development of NKp46 +cell populations in gut and skin. Nat. Immunol. 2009. 10: 7582.
  • 32
    Hughes, T., Becknell, B., McClory, S., Briercheck, E., Freud, A. G., Zhang, X., Mao, H., et al., Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH 17 cytokine interleukin-22. Blood 2009. 113: 40084010.
  • 33
    Crellin, N. K., Trifari, S., Kaplan, C. D., Cupedo, T. and Spits, H., Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J. Exp. Med. 2010. 207: 281290.
  • 34
    Cella, M., Fuchs, A., Vermi, W., Facchetti, F., Otero, K., Lennerz, J. K., Doherty, J. M., et al., A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 2009. 457: 722725.
  • 35
    Sanos, S. L., Bui, V. L., Mortha, A., Oberle, K., Heners, C., Johner, C. and Diefenbach, A., RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol. 2009. 10: 8391.
  • 36
    Simmons, C. P., Clare, S., Ghaem-Maghami, M., Uren, T. K., Rankin, J., Huett, A., Goldin, R., et al., Central role for B lymphocytes and CD4+ T cells in immunity to infection by the attaching and effacing pathogen Citrobacter rodentium. Infect. Immun. 2003. 71: 50775086.
  • 37
    Zheng, Y., Valdez, P. A., Danilenko, D. M., Hu, Y., Sa, S. M., Gong, Q., Abbas, A. R., et al., Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 2008. 14: 282289.
  • 38
    Sonnenberg, G. F., Monticelli, L. A., Elloso, M. M., Fouser, L. A. and Artis, D., CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 2011. 34: 122134.
  • 39
    Crellin, N. K., Trifari, S., Kaplan, C. D., Satoh-Takayama, N., Di Santo, J. P. and Spits, H., Regulation of cytokine secretion in human CD127(+) LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity 2010. 33: 752764.
  • 40
    Hughes, T., Becknell, B., Freud, A. G., McClory, S., Briercheck, E., Yu, J., Mao, C., Giovenzana, C., Nuovo, G., Wei, L., Zhang, X., Gavrilin, M. A., Wewers, M. D. and Caligiuri, M. A., Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue. Immunity 2010. 32: 803814.
  • 41
    Buonocore, S., Ahern, P. P., Uhlig, H. H., Ivanov, II, Littman, D. R., Maloy, K. J. and Powrie, F., Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 2010. 464: 13711375.
  • 42
    Jetten, A. M., Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl. Recept. Signal 2009. 7: e003.
  • 43
    Wang, Y., Kumar, N., Crumbley, C., Griffin, P. R. and Burris, T. P., A second class of nuclear receptors for oxysterols: Regulation of RORalpha and RORgamma activity by 24S-hydroxycholesterol (cerebrosterol). Biochim. Biophys Acta 2010. 1801: 917923.
  • 44
    Solt, L. A., Griffin, P. R. and Burris, T. P., Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics. Curr. Opin. Lipidol. 2010. 21: 204211.
  • 45
    Ivanov, II, McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J. and Littman, D. R., The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006. 126: 11211133.
  • 46
    Michel, M. L., Mendes-da-Cruz, D., Keller, A. C., Lochner, M., Schneider, E., Dy, M., Eberl, G. and Leite-de-Moraes, M. C., Critical role of ROR-gammat in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation. Proc. Natl. Acad. Sci. U. S. A. 2008. 105: 1984519850.
  • 47
    Lochner, M., Peduto, L., Cherrier, M., Sawa, S., Langa, F., Varona, R., Riethmacher, D., et al., In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J. Exp. Med. 2008. 205: 13811393.
  • 48
    Veldhoen, M. and Duarte, J. H., The aryl hydrocarbon receptor: fine-tuning the immune-response. Curr. Opin. Immunol. 2010. 22: 747752.
  • 49
    Veldhoen, M., Hirota, K., Westendorf, A. M., Buer, J., Dumoutier, L., Renauld, J. C. and Stockinger, B., The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 2008. 453: 106109.
  • 50
    Quintana, F. J., Basso, A. S., Iglesias, A. H., Korn, T., Farez, M. F., Bettelli, E., Caccamo, M., et al., Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008. 453: 6571.
  • 51
    Nakahama, T., Kimura, A., Nguyen, N. T., Chinen, I., Hanieh, H., Nohara, K., Fujii-Kuriyama, Y. and Kishimoto, T., Aryl hydrocarbon receptor deficiency in T cells suppresses the development of collagen-induced arthritis. Proc. Natl. Acad. Sci. U. S. A. 2011. 108: 1422214227.
  • 52
    Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K. and Spits, H., Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat. Immunol. 2009. 10: 864871.
  • 53
    Li, Y., Innocentin, S., Withers, D. R., Roberts, N. A., Gallagher, A. R., Grigorieva, E. F., Wilhelm, C. and Veldhoen, M., Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 2011. 147: 629640.
  • 54
    Qiu, J., Heller, J. J., Guo, X., Chen, Z. M., Fish, K., Fu, Y. X. and Zhou, L., The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 2011. 36: 92104.
  • 55
    Kiss, E. A., Vonarbourg, C., Kopfmann, S., Hobeika, E., Finke, D., Esser, C. and Diefenbach, A., Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 2011. 334: 15611565.
  • 56
    Lee, J. S., Cella, M., McDonald, K. G., Garlanda, C., Kennedy, G. D., Nukaya, M., Mantovani, A., et al., AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 2011. 13: 144151.
  • 57
    Sawa, S., Cherrier, M., Lochner, M., Satoh-Takayama, N., Fehling, H. J., Langa, F., Di Santo, J. P. and Eberl, G., Lineage relationship analysis of RORgammat+ innate lymphoid cells. Science 2010. 330: 665669.
  • 58
    Possot, C., Schmutz, S., Chea, S., Boucontet, L., Louise, A., Cumano, A. and Golub, R., Notch signaling is necessary for adult, but not fetal, development of RORgammat(+) innate lymphoid cells. Nat. Immunol. 2011. 12: 949958.
  • 59
    Hurst, S. D., Muchamuel, T., Gorman, D. M., Gilbert, J. M., Clifford, T., Kwan, S., Menon, S., et al., New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol. 2002. 169: 443453.
  • 60
    Fort, M. M., Cheung, J., Yen, D., Li, J., Zurawski, S. M., Lo, S., Menon, S., et al., IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 2001. 15: 985995.
  • 61
    Price, A. E., Liang, H. E., Sullivan, B. M., Reinhardt, R. L., Eisley, C. J., Erle, D. J. and Locksley, R. M., Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl. Acad. Sci. U. S. A. 2010. 107: 1148911494.
  • 62
    Neill, D. R., Wong, S. H., Bellosi, A., Flynn, R. J., Daly, M., Langford, T. K., Bucks, C., et al., Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464: 13671370.
  • 63
    Halim, T. Y., Krauss, R. H., Sun, A. C. and Takei, F., Lung natural helper cells are a critical source of th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 2012. 36: 451463.
  • 64
    Yang, Q., Saenz, S. A., Zlotoff, D. A., Artis, D. and Bhandoola, A., Cutting edge: Natural helper cells derive from lymphoid progenitors. J. Immunol. 2011. 187: 55055509.
  • 65
    Liang, H. E., Reinhardt, R. L., Bando, J. K., Sullivan, B. M., Ho, I. C. and Locksley, R. M., Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat. Immunol. 2011. 13: 5866.
  • 66
    Neill, D. R., Wong, S. H., Bellosi, A., Flynn, R. J., Daly, M., Langford, T. K., Bucks, C., et al., Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 2010. 464: 13671370.
  • 67
    Huh, J. R., Leung, M. W., Huang, P., Ryan, D. A., Krout, M. R., Malapaka, R. R., Chow, J., et al., Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 2011. 472: 486490.
  • 68
    Solt, L. A., Kumar, N., Nuhant, P., Wang, Y., Lauer, J. L., Liu, J., Istrate, M. A., et al., Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 2011. 472: 491494.