The Development and Diversity of ILCs, NK Cells and Their Relevance in Health and Diseases

  • Yuxia ZhangEmail author
  • Bing Huang
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1024)


Next to T and B cells, natural killer (NK) cells are the third largest lymphocyte population. They are recently re-categorized as innate lymphocytes (ILCs), which also include ILC1, ILC2, ILC3, and the lymphoid tissue inducer (LTi) cells. Both NK cells and ILC1 cells are designated as group 1 ILCs because they secrete interferon-γ (IFN-γ) and tumor necrosis factor (TNF). However, in contrast to ILC1 and all other ILCs, NK cells possess potent cytolytic functions that resemble cytotoxic T lymphocytes (CTL). In addition, NK cells express, in a stochastic manner, an array of germ line-encoded activating and inhibitory receptors that recognize the polymorphic regions of major histocompatibility class I (MHC-I) molecules and self-proteins. Recognition of self renders NK cell tolerance to self-healthy tissues, but fail to recognize self (‘missing-self’) leads to activation to neoplastic transformation and infections of certain viruses. In this chapter, we will summarize the development of NK cells in the context of ILCs, describe the diversity of phenotype and function in blood and tissues, and discuss their involvement in health and diseases in humans.


NK cells Development NK receptors Human disease 



Common helper ILC precursor


Common lymphoid progenitor


Cytotoxic T lymphocytes


Earliest ILC progenitors




ETS proto-oncogene 1


GATA-binding protein 3


Inhibitor of DNA binding 2


Interferon gamma


Innate lymphocyte


ILC progenitors


Janus kinase 1/3


Lymphoid tissue inducer cells


Murine cytomegalovirus


Myeloid elf-1-like factor


Major histocompatibility class I


Mechanistic target of rapamycin


Nuclear factor interleukin 3


Natural killer


Programmed cell death-1


3′-Phosphoinositide-dependent kinase 1


Promyelocytic leukemia zinc finger


Sphingosine-1-phosphate receptor 1


T-cell-specific T-box transcription factor


T-cell factor 1


Tumor necrosis factor


Thymocyte selection-associated high-mobility group box


TNF-related apoptosis ligand


Zinc finger E-box-binding homeobox 2



Y.Z. is supported by the Guangzhou Women and Children’s Medical Center Start-up Fund (5001-3001032).


  1. 1.
    Kiessling R, Klein E, Wigzell H (1975) “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol 5:112–117CrossRefPubMedGoogle Scholar
  2. 2.
    Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, Mckenzie AN, Mebius RE, Powrie F, Vivier E (2013) Innate lymphoid cells—a proposal for uniform nomenclature. Nat Rev Immunol 13:145–149PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Mebius RE, Rennert P, Weissman IL (1997) 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 7:493–504PubMedCrossRefGoogle Scholar
  4. 4.
    Chea S, Schmutz S, Berthault C, Perchet T, Petit M, Burlen-Defranoux O, Goldrath AW, Rodewald HR, Cumano A, Golub R (2016) Single-cell gene expression analyses reveal heterogeneous responsiveness of fetal innate lymphoid progenitors to notch signaling. Cell Rep 14:1500–1516PubMedCrossRefGoogle Scholar
  5. 5.
    Ishizuka IE, Chea S, Gudjonson H, Constantinides MG, Dinner AR, Bendelac A, Golub R (2016) Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue-inducer cell lineage. Nat Immunol 17:269–276PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Constantinides MG, Mcdonald BD, Verhoef PA, Bendelac A (2014) A committed precursor to innate lymphoid cells. Nature 508:397–401PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Klose CS, Flach M, Mohle L, Rogell L, Hoyler T, Ebert K, Fabiunke C, Pfeifer D, Sexl V, Fonseca-Pereira D, Domingues RG, Veiga-Fernandes H, Arnold SJ, Busslinger M, Dunay IR, Tanriver Y, Diefenbach A (2014) Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157:340–356PubMedCrossRefGoogle Scholar
  8. 8.
    Yu X, Wang Y, Deng M, Li Y, Ruhn KA, Zhang CC, Hooper LV (2014) The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. Elife 3Google Scholar
  9. 9.
    Vivier E, Van De Pavert SA, Cooper MD, Belz GT (2016) The evolution of innate lymphoid cells. Nat Immunol 17:790–794PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Diefenbach A, Colonna M, Romagnani C (2017) The ILC world revisited. Immunity 46:327–332PubMedCrossRefGoogle Scholar
  11. 11.
    Seillet C, Mielke LA, Amann-Zalcenstein DB, Su S, Gao J, Almeida FF, Shi W, Ritchie ME, Naik SH, Huntington ND, Carotta S, Belz GT (2016) Deciphering the innate lymphoid cell transcriptional program. Cell Rep 17:436–447PubMedCrossRefGoogle Scholar
  12. 12.
    Geiger TL, Abt MC, Gasteiger G, Firth MA, O'connor MH, Geary CD, O'sullivan TE, Van Den Brink MR, Pamer EG, Hanash AM, Sun JC (2014) Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J Exp Med 211:1723–1731PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Seillet C, Rankin LC, Groom JR, Mielke LA, Tellier J, Chopin M, Huntington ND, Belz GT, Carotta S (2014b) Nfil3 is required for the development of all innate lymphoid cell subsets. J Exp Med 211:1733–1740PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Xu W, Domingues RG, Fonseca-Pereira D, Ferreira M, Ribeiro H, Lopez-Lastra S, Motomura Y, Moreira-Santos L, Bihl F, Braud V, Kee B, Brady H, Coles MC, Vosshenrich C, Kubo M, Di Santo JP, Veiga-Fernandes H (2015) NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Rep 10:2043–2054PubMedCrossRefGoogle Scholar
  15. 15.
    Male V, Nisoli I, Kostrzewski T, Allan DS, Carlyle JR, Lord GM, Wack A, Brady HJ (2014) The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression. J Exp Med 211:635–642PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Mielke LA, Groom JR, Rankin LC, Seillet C, Masson F, Putoczki T, Belz GT (2013) TCF-1 controls ILC2 and NKp46+RORgammat+ innate lymphocyte differentiation and protection in intestinal inflammation. J Immunol 191:4383–4391PubMedCrossRefGoogle Scholar
  17. 17.
    Yang Q, Li F, Harly C, Xing S, Ye L, Xia X, Wang H, Wang X, Yu S, Zhou X, Cam M, Xue HH, Bhandoola A (2015b) TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat Immunol 16:1044–1050PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Yang Q, Monticelli LA, Saenz SA, Chi AW, Sonnenberg GF, Tang J, De Obaldia ME, Bailis W, Bryson JL, Toscano K, Huang J, Haczku A, Pear WS, Artis D, Bhandoola A (2013) T cell factor 1 is required for group 2 innate lymphoid cell generation. Immunity 38:694–704PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Klose CS, Kiss EA, Schwierzeck V, Ebert K, Hoyler T, D'hargues Y, Goppert N, Croxford AL, Waisman A, Tanriver Y, Diefenbach A (2013) A T-bet gradient controls the fate and function of CCR6-RORgammat+ innate lymphoid cells. Nature 494:261–265PubMedCrossRefGoogle Scholar
  20. 20.
    Seehus CR, Aliahmad P, De La Torre B, Iliev ID, Spurka L, Funari VA, Kaye J (2015) The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor. Nat Immunol 16:599–608PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Carotta S, Pang SH, Nutt SL, Belz GT (2011) Identification of the earliest NK-cell precursor in the mouse BM. Blood 117:5449–5452PubMedCrossRefGoogle Scholar
  22. 22.
    Fathman JW, Bhattacharya D, Inlay MA, Seita J, Karsunky H, Weissman IL (2011) Identification of the earliest natural killer cell-committed progenitor in murine bone marrow. Blood 118:5439–5447PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Eckelhart E, Warsch W, Zebedin E, Simma O, Stoiber D, Kolbe T, Rulicke T, Mueller M, Casanova E, Sexl V (2011) A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK-cell survival and development. Blood 117:1565–1573PubMedCrossRefGoogle Scholar
  24. 24.
    Nandagopal N, Ali AK, Komal AK, Lee SH (2014) The critical role of IL-15-PI3K-mTOR pathway in natural killer cell effector functions. Front Immunol 5:187PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Park SY, Saijo K, Takahashi T, Osawa M, Arase H, Hirayama N, Miyake K, Nakauchi H, Shirasawa T, Saito T (1995) Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity 3:771–782PubMedCrossRefGoogle Scholar
  26. 26.
    Yang M, Li D, Chang Z, Yang Z, Tian Z, Dong Z (2015a) PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness. J Exp Med 212:253–265PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Babic M, Pyzik M, Zafirova B, Mitrovic M, Butorac V, Lanier LL, Krmpotic A, Vidal SM, Jonjic S (2010) Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo. J Exp Med 207:2663–2673PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Lanier LL (2008) Evolutionary struggles between NK cells and viruses. Nat Rev Immunol 8:259–268PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kim S, Iizuka K, Kang HS, Dokun A, French AR, Greco S, Yokoyama WM (2002) In vivo developmental stages in murine natural killer cell maturation. Nat Immunol 3:523–528PubMedCrossRefGoogle Scholar
  30. 30.
    Van Helden MJ, Goossens S, Daussy C, Mathieu AL, Faure F, Marcais A, Vandamme N, Farla N, Mayol K, Viel S, Degouve S, Debien E, Seuntjens E, Conidi A, Chaix J, Mangeot P, De Bernard S, Buffat L, Haigh JJ, Huylebroeck D, Lambrecht BN, Berx G, Walzer T (2015) Terminal NK cell maturation is controlled by concerted actions of T-bet and Zeb2 and is essential for melanoma rejection. J Exp Med 212:2015–2025PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Chiossone L, Chaix J, Fuseri N, Roth C, Vivier E, Walzer T (2009) Maturation of mouse NK cells is a 4-stage developmental program. Blood 113:5488–5496PubMedCrossRefGoogle Scholar
  32. 32.
    Hayakawa Y, Smyth MJ (2006) CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J Immunol 176:1517–1524PubMedCrossRefGoogle Scholar
  33. 33.
    Seillet C, Huntington ND, Gangatirkar P, Axelsson E, Minnich M, Brady HJ, Busslinger M, Smyth MJ, Belz GT, Carotta S (2014a) Differential requirement for Nfil3 during NK cell development. J Immunol 192:2667–2676PubMedCrossRefGoogle Scholar
  34. 34.
    Barton K, Muthusamy N, Fischer C, Ting CN, Walunas TL, Lanier LL, Leiden JM (1998) The Ets-1 transcription factor is required for the development of natural killer cells in mice. Immunity 9:555–563PubMedCrossRefGoogle Scholar
  35. 35.
    Lee KN, Kang HS, Jeon JH, Kim EM, Yoon SR, Song H, Lyu CY, Piao ZH, Kim SU, Han YH, Song SS, Lee YH, Song KS, Kim YM, Yu DY, Choi I (2005) VDUP1 is required for the development of natural killer cells. Immunity 22:195–208PubMedCrossRefGoogle Scholar
  36. 36.
    Ramirez K, Chandler KJ, Spaulding C, Zandi S, Sigvardsson M, Graves BJ, Kee BL (2012) Gene deregulation and chronic activation in natural killer cells deficient in the transcription factor ETS1. Immunity 36:921–932PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Boos MD, Yokota Y, Eberl G, Kee BL (2007) Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J Exp Med 204:1119–1130PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Delconte RB, Shi W, Sathe P, Ushiki T, Seillet C, Minnich M, Kolesnik TB, Rankin LC, Mielke LA, Zhang JG, Busslinger M, Smyth MJ, Hutchinson DS, Nutt SL, Nicholson SE, Alexander WS, Corcoran LM, Vivier E, Belz GT, Carotta S, Huntington ND (2016) The helix-loop-helix protein ID2 governs NK cell fate by tuning their sensitivity to interleukin-15. Immunity 44:103–115PubMedCrossRefGoogle Scholar
  39. 39.
    Huntington ND, Puthalakath H, Gunn P, Naik E, Michalak EM, Smyth MJ, Tabarias H, Degli-Esposti MA, Dewson G, Willis SN, Motoyama N, Huang DC, Nutt SL, Tarlinton DM, Strasser A (2007) Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat Immunol 8:856–863PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Sathe P, Delconte RB, Souza-Fonseca-Guimaraes F, Seillet C, Chopin M, Vandenberg CJ, Rankin LC, Mielke LA, Vikstrom I, Kolesnik TB, Nicholson SE, Vivier E, Smyth MJ, Nutt SL, Glaser SP, Strasser A, Belz GT, Carotta S, Huntington ND (2014) Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells. Nat Commun 5:4539PubMedCrossRefGoogle Scholar
  41. 41.
    Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC, Lindsten T, Reiner SL (2012) The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36:55–67PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Sojka DK, Plougastel-Douglas B, Yang L, Pak-Wittel MA, Artyomov MN, Ivanova Y, Zhong C, Chase JM, Rothman PB, Yu J, Riley JK, Zhu J, Tian Z, Yokoyama WM (2014) Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife 3:e01659PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Lacorazza HD, Miyazaki Y, Di Cristofano A, Deblasio A, Hedvat C, Zhang J, Cordon-Cardo C, Mao S, Pandolfi PP, Nimer SD (2002) The ETS protein MEF plays a critical role in perforin gene expression and the development of natural killer and NK-T cells. Immunity 17:437–449PubMedCrossRefGoogle Scholar
  44. 44.
    Colucci F, Samson SI, Dekoter RP, Lantz O, Singh H, Di Santo JP (2001) Differential requirement for the transcription factor PU.1 in the generation of natural killer cells versus B and T cells. Blood 97:2625–2632PubMedCrossRefGoogle Scholar
  45. 45.
    Kallies A, Carotta S, Huntington ND, Bernard NJ, Tarlinton DM, Smyth MJ, Nutt SL (2011) A role for Blimp1 in the transcriptional network controlling natural killer cell maturation. Blood 117:1869–1879PubMedCrossRefGoogle Scholar
  46. 46.
    Aliahmad P, De La Torre B, Kaye J (2010) Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nat Immunol 11:945–952PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Holmes ML, Huntington ND, Thong RP, Brady J, Hayakawa Y, Andoniou CE, Fleming P, Shi W, Smyth GK, Degli-Esposti MA, Belz GT, Kallies A, Carotta S, Smyth MJ, Nutt SL (2014) Peripheral natural killer cell maturation depends on the transcription factor Aiolos. EMBO J 33:2721–2734PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Rabacal W, Pabbisetty SK, Hoek KL, Cendron D, Guo Y, Maseda D, Sebzda E (2016) Transcription factor KLF2 regulates homeostatic NK cell proliferation and survival. Proc Natl Acad Sci USA 113:5370–5375PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Samson SI, Richard O, Tavian M, Ranson T, Vosshenrich CA, Colucci F, Buer J, Grosveld F, Godin I, Di Santo JP (2003) GATA-3 promotes maturation, IFN-gamma production, and liver-specific homing of NK cells. Immunity 19:701–711PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ali AK, Oh JS, Vivier E, Busslinger M, Lee SH (2016) NK cell-specific Gata3 ablation identifies the maturation program required for bone marrow exit and control of proliferation. J Immunol 196:1753–1767PubMedCrossRefGoogle Scholar
  51. 51.
    Wang S, Xia P, Huang G, Zhu P, Liu J, Ye B, Du Y, Fan Z (2016) FoxO1-mediated autophagy is required for NK cell development and innate immunity. Nat Commun 7:11023PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Deng Y, Kerdiles Y, Chu J, Yuan S, Wang Y, Chen X, Mao H, Zhang L, Zhang J, Hughes T, Deng Y, Zhang Q, Wang F, Zou X, Liu CG, Freud AG, Li X, Caligiuri MA, Vivier E, Yu J (2015) Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function. Immunity 42:457–470PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Shiow LR, Rosen DB, Brdickova N, Xu Y, An J, Lanier LL, Cyster JG, Matloubian M (2006) CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440:540–544PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Walzer T, Chiossone L, Chaix J, Calver A, Carozzo C, Garrigue-Antar L, Jacques Y, Baratin M, Tomasello E, Vivier E (2007) Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat Immunol 8:1337–1344PubMedCrossRefGoogle Scholar
  55. 55.
    Cepek KL, Shaw SK, Parker CM, Russell GJ, Morrow JS, Rimm DL, Brenner MB (1994) Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 372:190–193PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Kramer RH, Marks N (1989) Identification of integrin collagen receptors on human melanoma cells. J Biol Chem 264:4684–4688PubMedGoogle Scholar
  57. 57.
    Cerdeira AS, Rajakumar A, Royle CM, Lo A, Husain Z, Thadhani RI, Sukhatme VP, Karumanchi SA, Kopcow HD (2013) Conversion of peripheral blood NK cells to a decidual NK-like phenotype by a cocktail of defined factors. J Immunol 190:3939–3948PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Cortez VS, Fuchs A, Cella M, Gilfillan S, Colonna M (2014) Cutting edge: salivary gland NK cells develop independently of Nfil3 in steady-state. J Immunol 192:4487–4491PubMedCrossRefGoogle Scholar
  59. 59.
    Boulenouar S, Doisne JM, Sferruzzi-Perri A, Gaynor LM, Kieckbusch J, Balmas E, Yung HW, Javadzadeh S, Volmer L, Hawkes DA, Phillips K, Brady HJ, Fowden AL, Burton GJ, Moffett A, Colucci F (2016) The residual innate lymphoid cells in NFIL3-deficient mice support suboptimal maternal adaptations to pregnancy. Front Immunol 7:43PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Montaldo E, Vacca P, Chiossone L, Croxatto D, Loiacono F, Martini S, Ferrero S, Walzer T, Moretta L, Mingari MC (2015) Unique Eomes(+) NK cell subsets are present in uterus and decidua during early pregnancy. Front Immunol 6:646PubMedGoogle Scholar
  61. 61.
    Tayade C, Fang Y, Black GP, Paffaro VA Jr, Erlebacher A, Croy BA (2005) Differential transcription of Eomes and T-bet during maturation of mouse uterine natural killer cells. J Leukoc Biol 78:1347–1355PubMedCrossRefGoogle Scholar
  62. 62.
    Ribeiro VS, Hasan M, Wilson A, Boucontet L, Pereira P, Lesjean-Pottier S, Satoh-Takayama N, Di Santo JP, Vosshenrich CA (2010) Cutting edge: thymic NK cells develop independently from T cell precursors. J Immunol 185:4993–4997PubMedCrossRefGoogle Scholar
  63. 63.
    Vosshenrich CA, Garcia-Ojeda ME, Samson-Villeger SI, Pasqualetto V, Enault L, Richard-Le Goff O, Corcuff E, Guy-Grand D, Rocha B, Cumano A, Rogge L, Ezine S, Di Santo JP (2006) A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat Immunol 7:1217–1224PubMedCrossRefGoogle Scholar
  64. 64.
    Manser AR, Weinhold S, Uhrberg M (2015) Human KIR repertoires: shaped by genetic diversity and evolution. Immunol Rev 267:178–196PubMedCrossRefGoogle Scholar
  65. 65.
    Orr MT, Lanier LL (2010) Natural killer cell education and tolerance. Cell 142:847–856PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Rahim MM, Makrigiannis AP (2015) Ly49 receptors: evolution, genetic diversity, and impact on immunity. Immunol Rev 267:137–147PubMedCrossRefGoogle Scholar
  67. 67.
    Binstadt BA, Brumbaugh KM, Dick CJ, Scharenberg AM, Williams BL, Colonna M, Lanier LL, Kinet JP, Abraham RT, Leibson PJ (1996) Sequential involvement of Lck and SHP-1 with MHC-recognizing receptors on NK cells inhibits FcR-initiated tyrosine kinase activation. Immunity 5:629–638PubMedCrossRefGoogle Scholar
  68. 68.
    Long EO (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70–84PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Vivier E, Nunes JA, Vely F (2004) Natural killer cell signaling pathways. Science 306:1517–1519PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Chan CJ, Smyth MJ, Martinet L (2014) Molecular mechanisms of natural killer cell activation in response to cellular stress. Cell Death Differ 21:5–14PubMedCrossRefGoogle Scholar
  71. 71.
    Billadeau DD, Upshaw JL, Schoon RA, Dick CJ, Leibson PJ (2003) NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nat Immunol 4:557–564CrossRefPubMedGoogle Scholar
  72. 72.
    Zompi S, Hamerman JA, Ogasawara K, Schweighoffer E, Tybulewicz VL, Di Santo JP, Lanier LL, Colucci F (2003) NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases. Nat Immunol 4:565–572PubMedCrossRefGoogle Scholar
  73. 73.
    Quatrini L, Molfetta R, Zitti B, Peruzzi G, Fionda C, Capuano C, Galandrini R, Cippitelli M, Santoni A, Paolini R (2015) Ubiquitin-dependent endocytosis of NKG2D-DAP10 receptor complexes activates signaling and functions in human NK cells. Sci Signal 8:ra108PubMedCrossRefGoogle Scholar
  74. 74.
    Campbell KS, Purdy AK (2011) Structure/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations. Immunology 132:315–325PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Parham P (2005) MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 5:201–214PubMedCrossRefGoogle Scholar
  76. 76.
    Fang M, Orr MT, Spee P, Egebjerg T, Lanier LL, Sigal LJ (2011) CD94 is essential for NK cell-mediated resistance to a lethal viral disease. Immunity 34:579–589PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Orbelyan GA, Tang F, Sally B, Solus J, Meresse B, Ciszewski C, Grenier JC, Barreiro LB, Lanier LL, Jabri B (2014) Human NKG2E is expressed and forms an intracytoplasmic complex with CD94 and DAP12. J Immunol 193:610–616PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Wada H, Matsumoto N, Maenaka K, Suzuki K, Yamamoto K (2004) The inhibitory NK cell receptor CD94/NKG2A and the activating receptor CD94/NKG2C bind the top of HLA-E through mostly shared but partly distinct sets of HLA-E residues. Eur J Immunol 34:81–90PubMedCrossRefGoogle Scholar
  79. 79.
    Davidson CL, Li NL, Burshtyn DN (2010) LILRB1 polymorphism and surface phenotypes of natural killer cells. Hum Immunol 71:942–949PubMedCrossRefGoogle Scholar
  80. 80.
    He Y, Tian Z (2017) NK cell education via nonclassical MHC and non-MHC ligands. Cell Mol Immunol 14:321–330PubMedCrossRefGoogle Scholar
  81. 81.
    Lee KM, Forman JP, Mcnerney ME, Stepp S, Kuppireddi S, Guzior D, Latchman YE, Sayegh MH, Yagita H, Park CK, Oh SB, Wulfing C, Schatzle J, Mathew PA, Sharpe AH, Kumar V (2006) Requirement of homotypic NK-cell interactions through 2B4(CD244)/CD48 in the generation of NK effector functions. Blood 107:3181–3188PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Aldemir H, Prod’homme V, Dumaurier MJ, Retiere C, Poupon G, Cazareth J, Bihl F, Braud VM (2005) Cutting edge: lectin-like transcript 1 is a ligand for the CD161 receptor. J Immunol 175:7791–7795PubMedCrossRefGoogle Scholar
  83. 83.
    Rosen DB, Cao W, Avery DT, Tangye SG, Liu YJ, Houchins JP, Lanier LL (2008) Functional consequences of interactions between human NKR-P1A and its ligand LLT1 expressed on activated dendritic cells and B cells. J Immunol 180:6508–6517PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Li Y, Hofmann M, Wang Q, Teng L, Chlewicki LK, Pircher H, Mariuzza RA (2009) Structure of natural killer cell receptor KLRG1 bound to E-cadherin reveals basis for MHC-independent missing self recognition. Immunity 31:35–46PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Castells MC, Klickstein LB, Hassani K, Cumplido JA, Lacouture ME, Austen KF, Katz HR (2001) gp49B1-alpha(v)beta3 interaction inhibits antigen-induced mast cell activation. Nat Immunol 2:436–442PubMedCrossRefGoogle Scholar
  86. 86.
    Gu X, Laouar A, Wan J, Daheshia M, Lieberman J, Yokoyama WM, Katz HR, Manjunath N (2003) The gp49B1 inhibitory receptor regulates the IFN-gamma responses of T cells and NK cells. J Immunol 170:4095–4101PubMedCrossRefGoogle Scholar
  87. 87.
    Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, Cantoni C, Grassi J, Marcenaro S, Reymond N, Vitale M, Moretta L, Lopez M, Moretta A (2003) Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 198:557–567PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Chan CJ, Andrews DM, Mclaughlin NM, Yagita H, Gilfillan S, Colonna M, Smyth MJ (2010) DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases. J Immunol 184:902–911PubMedCrossRefGoogle Scholar
  89. 89.
    Pende D, Spaggiari GM, Marcenaro S, Martini S, Rivera P, Capobianco A, Falco M, Lanino E, Pierri I, Zambello R, Bacigalupo A, Mingari MC, Moretta A, Moretta L (2005) Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the poliovirus receptor (CD155) and Nectin-2 (CD112). Blood 105:2066–2073PubMedCrossRefGoogle Scholar
  90. 90.
    He Y, Peng H, Sun R, Wei H, Ljunggren HG, Yokoyama WM, Tian Z (2017) Contribution of inhibitory receptor TIGIT to NK cell education. J Autoimmun 81:1–12PubMedCrossRefGoogle Scholar
  91. 91.
    Stanietsky N, Simic H, Arapovic J, Toporik A, Levy O, Novik A, Levine Z, Beiman M, Dassa L, Achdout H, Stern-Ginossar N, Tsukerman P, Jonjic S, Mandelboim O (2009) The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA 106:17858–17863PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, French AR, Sunwoo JB, Lemieux S, Hansen TH, Yokoyama WM (2005) Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436:709–713PubMedCrossRefGoogle Scholar
  93. 93.
    Orr MT, Murphy WJ, Lanier LL (2010) ‘Unlicensed’ natural killer cells dominate the response to cytomegalovirus infection. Nat Immunol 11:321–327PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Yokoyama WM, Altfeld M, Hsu KC (2010) Natural killer cells: tolerance to self and innate immunity to viral infection and malignancy. Biol Blood Marrow Transplant 16:S97–S105PubMedCrossRefGoogle Scholar
  95. 95.
    Waldhauer I, Steinle A (2008) NK cells and cancer immunosurveillance. Oncogene 27:5932–5943PubMedCrossRefGoogle Scholar
  96. 96.
    Renoux VM, Zriwil A, Peitzsch C, Michaelsson J, Friberg D, Soneji S, Sitnicka E (2015) Identification of a human natural killer cell lineage-restricted progenitor in fetal and adult tissues. Immunity 43:394–407PubMedCrossRefGoogle Scholar
  97. 97.
    Bjorkstrom NK, Ljunggren HG, Michaelsson J (2016) Emerging insights into natural killer cells in human peripheral tissues. Nat Rev Immunol 16:310–320PubMedCrossRefGoogle Scholar
  98. 98.
    Juelke K, Killig M, Luetke-Eversloh M, Parente E, Gruen J, Morandi B, Ferlazzo G, Thiel A, Schmitt-Knosalla I, Romagnani C (2010) CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells. Blood 116:1299–1307PubMedCrossRefGoogle Scholar
  99. 99.
    Yu J, Mao HC, Wei M, Hughes T, Zhang J, Park IK, Liu S, Mcclory S, Marcucci G, Trotta R, Caligiuri MA (2010) CD94 surface density identifies a functional intermediary between the CD56bright and CD56dim human NK-cell subsets. Blood 115:274–281PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Carson WE, Fehniger TA, Caligiuri MA (1997) CD56bright natural killer cell subsets: characterization of distinct functional responses to interleukin-2 and the c-kit ligand. Eur J Immunol 27:354–360PubMedCrossRefGoogle Scholar
  101. 101.
    Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, Carson WE, Caligiuri MA (2001) Human natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subset. Blood 97:3146–3151PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Fauriat C, Long EO, Ljunggren HG, Bryceson YT (2010) Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood 115:2167–2176PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Bjorkstrom NK, Riese P, Heuts F, Andersson S, Fauriat C, Ivarsson MA, Bjorklund AT, Flodstrom-Tullberg M, Michaelsson J, Rottenberg ME, Guzman CA, Ljunggren HG, Malmberg KJ (2010) Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education. Blood 116:3853–3864PubMedCrossRefGoogle Scholar
  104. 104.
    Lopez-Verges S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H, Norris PJ, Nixon DF, Lanier LL (2010) CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. Blood 116:3865–3874PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Wilkens J, Male V, Ghazal P, Forster T, Gibson DA, Williams AR, Brito-Mutunayagam SL, Craigon M, Lourenco P, Cameron IT, Chwalisz K, Moffett A, Critchley HO (2013) Uterine NK cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil. J Immunol 191:2226–2235PubMedCrossRefGoogle Scholar
  106. 106.
    Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S, Prus D, Cohen-Daniel L, Arnon TI, Manaster I, Gazit R, Yutkin V, Benharroch D, Porgador A, Keshet E, Yagel S, Mandelboim O (2006) Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 12:1065–1074PubMedCrossRefGoogle Scholar
  107. 107.
    Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, Masch R, Lockwood CJ, Schachter AD, Park PJ, Strominger JL (2003) Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 198:1201–1212PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Kopcow HD, Allan DS, Chen X, Rybalov B, Andzelm MM, Ge B, Strominger JL (2005) Human decidual NK cells form immature activating synapses and are not cytotoxic. Proc Natl Acad Sci USA 102:15563–15568PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Sharkey AM, Xiong S, Kennedy PR, Gardner L, Farrell LE, Chazara O, Ivarsson MA, Hiby SE, Colucci F, Moffett A (2015) Tissue-specific education of decidual NK cells. J Immunol 195:3026–3032PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Racanelli V, Rehermann B (2006) The liver as an immunological organ. Hepatology 43:S54–S62PubMedCrossRefGoogle Scholar
  111. 111.
    Burt BM, Plitas G, Zhao Z, Bamboat ZM, Nguyen HM, Dupont B, Dematteo RP (2009) The lytic potential of human liver NK cells is restricted by their limited expression of inhibitory killer Ig-like receptors. J Immunol 183:1789–1796PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Marquardt N, Beziat V, Nystrom S, Hengst J, Ivarsson MA, Kekalainen E, Johansson H, Mjosberg J, Westgren M, Lankisch TO, Wedemeyer H, Ellis EC, Ljunggren HG, Michaelsson J, Bjorkstrom NK (2015) Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J Immunol 194:2467–2471PubMedCrossRefGoogle Scholar
  113. 113.
    Heydtmann M, Lalor PF, Eksteen JA, Hubscher SG, Briskin M, Adams DH (2005) CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. J Immunol 174:1055–1062PubMedCrossRefGoogle Scholar
  114. 114.
    Hudspeth K, Donadon M, Cimino M, Pontarini E, Tentorio P, Preti M, Hong M, Bertoletti A, Bicciato S, Invernizzi P, Lugli E, Torzilli G, Gershwin ME, Mavilio D (2016) Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J Autoimmun 66:40–50PubMedCrossRefGoogle Scholar
  115. 115.
    Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS (2008) TLR-dependent cross talk between human Kupffer cells and NK cells. J Exp Med 205:233–244PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Jo J, Tan AT, Ussher JE, Sandalova E, Tang XZ, Tan-Garcia A, To N, Hong M, Chia A, Gill US, Kennedy PT, Tan KC, Lee KH, De Libero G, Gehring AJ, Willberg CB, Klenerman P, Bertoletti A (2014) Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver. PLoS Pathog 10:e1004210PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Stegmann KA, Bjorkstrom NK, Veber H, Ciesek S, Riese P, Wiegand J, Hadem J, Suneetha PV, Jaroszewicz J, Wang C, Schlaphoff V, Fytili P, Cornberg M, Manns MP, Geffers R, Pietschmann T, Guzman CA, Ljunggren HG, Wedemeyer H (2010) Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology 138:1885–1897PubMedCrossRefGoogle Scholar
  118. 118.
    Dunn C, Brunetto M, Reynolds G, Christophides T, Kennedy PT, Lampertico P, Das A, Lopes AR, Borrow P, Williams K, Humphreys E, Afford S, Adams DH, Bertoletti A, Maini MK (2007) Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 204:667–680PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Peppa D, Gill US, Reynolds G, Easom NJ, Pallett LJ, Schurich A, Micco L, Nebbia G, Singh HD, Adams DH, Kennedy PT, Maini MK (2013) Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med 210:99–114PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Beziat V, Liu LL, Malmberg JA, Ivarsson MA, Sohlberg E, Bjorklund AT, Retiere C, Sverremark-Ekstrom E, Traherne J, Ljungman P, Schaffer M, Price DA, Trowsdale J, Michaelsson J, Ljunggren HG, Malmberg KJ (2013) NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs. Blood 121:2678–2688PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Guma M, Angulo A, Vilches C, Gomez-Lozano N, Malats N, Lopez-Botet M (2004) Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood 104:3664–3671PubMedCrossRefGoogle Scholar
  122. 122.
    Hendricks DW, Balfour HH Jr, Dunmire SK, Schmeling DO, Hogquist KA, Lanier LL (2014) Cutting edge: NKG2C(hi)CD57+ NK cells respond specifically to acute infection with cytomegalovirus and not Epstein-Barr virus. J Immunol 192:4492–4496PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, Houchins JP, Miller S, Kang SM, Norris PJ, Nixon DF, Lanier LL (2011) Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci USA 108:14725–14732PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Petitdemange C, Becquart P, Wauquier N, Beziat V, Debre P, Leroy EM, Vieillard V (2011) Unconventional repertoire profile is imprinted during acute chikungunya infection for natural killer cells polarization toward cytotoxicity. PLoS Pathog 7:e1002268PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Schlums H, Cichocki F, Tesi B, Theorell J, Beziat V, Holmes TD, Han H, Chiang SC, Foley B, Mattsson K, Larsson S, Schaffer M, Malmberg KJ, Ljunggren HG, Miller JS, Bryceson YT (2015) Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42:443–456 doi: 10.1371/journal.ppat.1002268 CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Bjorkstrom NK, Lindgren T, Stoltz M, Fauriat C, Braun M, Evander M, Michaelsson J, Malmberg KJ, Klingstrom J, Ahlm C, Ljunggren HG (2011) Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med 208:13–21PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Guangzhou Institute of Paediatrics, Guangzhou Women and Children’s Medical CentreGuangzhou Medical UniversityGuangzhouChina

Personalised recommendations