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Activating and inhibitory receptors expressed on innate lymphoid cells

Seminars in Immunopathology volume 40, pages 331–341 (2018)Cite this article

Abstract

Innate lymphoid cells (ILCs) are innate immune cells located in lymphoid and non-lymphoid tissues. They are particularly abundant at mucosal and barrier surfaces. Three major ILC subsets are present in humans and mice: group 1 ILCs (comprising natural killer (NK) cells and ILC1s), ILC2s, and ILC3s. ILCs are involved in the maintenance of homeostasis and the regulation of immunity. This review focuses on the extensive array of activating and inhibitory receptors expressed by ILCs for communication with other cell types and their environment in health and disease.

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References

  1. Tait Wojno ED, Artis D (2016) Emerging concepts and future challenges in innate lymphoid cell biology. J Exp Med 213(11):2229–2248

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. Spits H, Artis D, Colonna M, Diefenbach A, di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie A, Mebius RE, Powrie F, Vivier E (2013) Innate lymphoid cells—a proposal for uniform nomenclature. Nature reviews. Immunology 13(2):145–149

    PubMed  CAS  Google Scholar 

  3. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331(6013):44–49

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  4. Spits H, Bernink JH, Lanier L (2016) NK cells and type 1 innate lymphoid cells: partners in host defense. Nat Immunol 17(7):758–764

    PubMed  Article  CAS  Google Scholar 

  5. Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, Cesses P, Garnier L, Pouzolles M, Brulin B, Bruschi M, Harcus Y, Zimmermann VS, Taylor N, Maizels RM, Jay P (2016) Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529(7585):226–230

    PubMed  Article  CAS  Google Scholar 

  6. Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV, Gallini CA, Redding K, Margolskee RF, Osborne LC, Artis D, Garrett WS (2016) Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351(6279):1329–1333

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. von Moltke J, Ji M, Liang HE, Locksley RM (2016) Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529(7585):221–225

    Article  CAS  Google Scholar 

  8. Klose CSN, Flach M, Möhle 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(2):340–356

    PubMed  Article  CAS  Google Scholar 

  9. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TKA, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie ANJ (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464(7293):1367–1370

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. Motomura Y, Morita H, Moro K, Nakae S, Artis D, Endo TA, Kuroki Y, Ohara O, Koyasu S, Kubo M (2014) Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation. Immunity 40(5):758–771

    PubMed  Article  CAS  Google Scholar 

  11. Roediger B, Kyle R, Yip KH, Sumaria N, Guy TV, Kim BS, Mitchell AJ, Tay SS, Jain R, Forbes-Blom E, Chen X, Tong PL, Bolton HA, Artis D, Paul WE, de St Groth BF, Grimbaldeston MA, le Gros G, Weninger W (2013) Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol 14(6):564–573

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. Hughes T, Becknell B, Freud AG, McClory S, Briercheck E, Yu J, Mao C, Giovenzana C, Nuovo G, Wei L, Zhang X, Gavrilin MA, Wewers MD, Caligiuri MA (2010) Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue. Immunity 32(6):803–814

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, Abbas AR, Modrusan Z, Ghilardi N, de Sauvage FJ, Ouyang W (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14(3):282–289

    PubMed  Article  CAS  Google Scholar 

  14. Doherty TA, Khorram N, Lund S, Mehta AK, Croft M, Broide DH (2013) Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J Allergy Clin Immunol 132(1):205–213

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, Hepworth MR, van Voorhees A, Comeau MR, Artis D (2013) TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med 5(170):170ra16

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. Wojno ED et al (2015) The prostaglandin D(2) receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung. Mucosal Immunol 8(6):1313–1323

    PubMed  Article  CAS  Google Scholar 

  17. Klose CS, Artis D (2016) Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol 17(7):765–774

    PubMed  Article  CAS  Google Scholar 

  18. Narni-Mancinelli E, Ugolini S, Vivier E (2013) Tuning the threshold of natural killer cell responses. Curr Opin Immunol 25(1):53–58

    PubMed  Article  CAS  Google Scholar 

  19. Vivier E, Nunes JA, Vely F (2004) Natural killer cell signaling pathways. Science 306(5701):1517–1519

    PubMed  Article  CAS  Google Scholar 

  20. Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L (2001) Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 19:197–223

    PubMed  Article  CAS  Google Scholar 

  21. Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH (2011) Activating and inhibitory receptors of natural killer cells. Immunol Cell Biol 89(2):216–224

    PubMed  Article  Google Scholar 

  22. Tomasello E et al (2000) Signaling pathways engaged by NK cell receptors: double concerto for activating receptors, inhibitory receptors and NK cells. Semin Immunol 12(2):139–147

    PubMed  Article  CAS  Google Scholar 

  23. Rahim MM et al (2014) Ly49 receptors: innate and adaptive immune paradigms. Front Immunol 5:145

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. Aguilar OA et al (2017) A viral immunoevasin controls innate immunity by targeting the prototypical natural killer cell receptor family. Cell 169(1):58–71 e14

    PubMed  Article  CAS  Google Scholar 

  25. Arnon TI et al (2001) Recognition of viral hemagglutinins by NKp44 but not by NKp30. Eur J Immunol 31(9):2680–2689

    PubMed  Article  CAS  Google Scholar 

  26. Jarahian M, Watzl C, Fournier P, Arnold A, Djandji D, Zahedi S, Cerwenka A, Paschen A, Schirrmacher V, Momburg F (2009) Activation of natural killer cells by Newcastle disease virus hemagglutinin-neuraminidase. J Virol 83(16):8108–8121

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. Mandelboim O, Lieberman N, Lev M, Paul L, Arnon TI, Bushkin Y, Davis DM, Strominger JL, Yewdell JW, Porgador A (2001) Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409(6823):1055–1060

    PubMed  Article  CAS  Google Scholar 

  28. Chisholm SE, Reyburn HT (2006) Recognition of vaccinia virus-infected cells by human natural killer cells depends on natural cytotoxicity receptors. J Virol 80(5):2225–2233

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. Jarahian M, Fiedler M, Cohnen A, Djandji D, Hämmerling GJ, Gati C, Cerwenka A, Turner PC, Moyer RW, Watzl C, Hengel H, Momburg F (2011) Modulation of NKp30- and NKp46-mediated natural killer cell responses by poxviral hemagglutinin. PLoS Pathog 7(8):e1002195

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. Achdout H, Meningher T, Hirsh S, Glasner A, Bar-On Y, Gur C, Porgador A, Mendelson M, Mandelboim M, Mandelboim O (2010) Killing of avian and swine influenza virus by natural killer cells. J Virol 84(8):3993–4001

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. Mendelson M, Tekoah Y, Zilka A, Gershoni-Yahalom O, Gazit R, Achdout H, Bovin NV, Meningher T, Mandelboim M, Mandelboim O, David A, Porgador A (2010) NKp46 O-glycan sequences that are involved in the interaction with hemagglutinin type 1 of influenza virus. J Virol 84(8):3789–3797

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. Mao H, Tu W, Liu Y, Qin G, Zheng J, Chan PL, Lam KT, Peiris JSM, Lau YL (2010) Inhibition of human natural killer cell activity by influenza virions and hemagglutinin. J Virol 84(9):4148–4157

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. Gazit R, Gruda R, Elboim M, Arnon TI, Katz G, Achdout H, Hanna J, Qimron U, Landau G, Greenbaum E, Zakay-Rones Z, Porgador A, Mandelboim O (2006) Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nat Immunol 7(5):517–523

    PubMed  Article  CAS  Google Scholar 

  34. Ho JW, Hershkovitz O, Peiris M, Zilka A, Bar-Ilan A, Nal B, Chu K, Kudelko M, Kam YW, Achdout H, Mandelboim M, Altmeyer R, Mandelboim O, Bruzzone R, Porgador A (2008) H5-type influenza virus hemagglutinin is functionally recognized by the natural killer-activating receptor NKp44. J Virol 82(4):2028–2032

    PubMed  Article  CAS  Google Scholar 

  35. Hershkovitz O, Rosental B, Rosenberg LA, Navarro-Sanchez ME, Jivov S, Zilka A, Gershoni-Yahalom O, Brient-Litzler E, Bedouelle H, Ho JW, Campbell KS, Rager-Zisman B, Despres P, Porgador A (2009) NKp44 receptor mediates interaction of the envelope glycoproteins from the West Nile and dengue viruses with NK cells. J Immunol 183(4):2610–2621

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. Arnon TI, Achdout H, Levi O, Markel G, Saleh N, Katz G, Gazit R, Gonen-Gross T, Hanna J, Nahari E, Porgador A, Honigman A, Plachter B, Mevorach D, Wolf DG, Mandelboim O (2005) Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat Immunol 6(5):515–523

    PubMed  Article  CAS  Google Scholar 

  37. Muller TF et al (2002) Pattern and persistence of the epitope-specific IgM response against human cytomegalovirus in renal transplant patients. J Clin Virol 24(1–2):45–56

    PubMed  Article  CAS  Google Scholar 

  38. Bar-On Y, Charpak-Amikam Y, Glasner A, Isaacson B, Duev-Cohen A, Tsukerman P, Varvak A, Mandelboim M, Mandelboim O (2017) NKp46 recognizes the sigma1 protein of reovirus: implications for reovirus-based cancer therapy. J Virol 91:e01045–e01017

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. Esin S, Batoni G, Pardini M, Favilli F, Bottai D, Maisetta G, Florio W, Vanacore R, Wigzell H, Campa M (2004) Functional characterization of human natural killer cells responding to Mycobacterium bovis bacille Calmette-Guerin. Immunology 112(1):143–152

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. Esin S, Batoni G, Counoupas C, Stringaro A, Brancatisano FL, Colone M, Maisetta G, Florio W, Arancia G, Campa M (2008) Direct binding of human NK cell natural cytotoxicity receptor NKp44 to the surfaces of mycobacteria and other bacteria. Infect Immun 76(4):1719–1727

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Esin S, Counoupas C, Aulicino A, Brancatisano FL, Maisetta G, Bottai D, di Luca M, Florio W, Campa M, Batoni G (2013) Interaction of Mycobacterium tuberculosis cell wall components with the human natural killer cell receptors NKp44 and Toll-like receptor 2. Scand J Immunol 77(6):460–469

    PubMed  Article  CAS  Google Scholar 

  42. Chaushu S, Wilensky A, Gur C, Shapira L, Elboim M, Halftek G, Polak D, Achdout H, Bachrach G, Mandelboim O (2012) Direct recognition of Fusobacterium nucleatum by the NK cell natural cytotoxicity receptor NKp46 aggravates periodontal disease. PLoS Pathog 8(3):e1002601

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Mavoungou E, Held J, Mewono L, Kremsner PG (2007) A Duffy binding-like domain is involved in the NKp30-mediated recognition of Plasmodium falciparum-parasitized erythrocytes by natural killer cells. J Infect Dis 195(10):1521–1531

    PubMed  Article  CAS  Google Scholar 

  44. Baratin M, Roetynck S, Lepolard C, Falk C, Sawadogo S, Uematsu S, Akira S, Ryffel B, Tiraby JG, Alexopoulou L, Kirschning CJ, Gysin J, Vivier E, Ugolini S (2005) Natural killer cell and macrophage cooperation in MyD88-dependent innate responses to Plasmodium falciparum. Proc Natl Acad Sci U S A 102(41):14747–14752

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. Baratin M, Roetynck S, Pouvelle B, Lemmers C, Viebig NK, Johansson S, Bierling P, Scherf A, Gysin J, Vivier E, Ugolini S (2007) Dissection of the role of PfEMP1 and ICAM-1 in the sensing of Plasmodium falciparum-infected erythrocytes by natural killer cells. PLoS One 2(2):e228

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. Ziegler S, Weiss E, Schmitt AL, Schlegel J, Burgert A, Terpitz U, Sauer M, Moretta L, Sivori S, Leonhardt I, Kurzai O, Einsele H, Loeffler J (2017) CD56 is a pathogen recognition receptor on human natural killer cells. Sci Rep 7(1):6138

    PubMed  PubMed Central  Article  Google Scholar 

  47. Bryceson YT, March ME, Ljunggren HG, Long EO (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73–91

    PubMed  Article  CAS  Google Scholar 

  48. Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L, Marcenaro E, Accame L, Malaspina A, Biassoni R, Bottino C, Moretta L, Moretta A (1999) Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med 190(10):1505–1516

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. Garcia-Beltran WF, Hölzemer A, Martrus G, Chung AW, Pacheco Y, Simoneau CR, Rucevic M, Lamothe-Molina PA, Pertel T, Kim TE, Dugan H, Alter G, Dechanet-Merville J, Jost S, Carrington M, Altfeld M (2016) Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol 17(9):1067–1074

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. Crinier A et al (2017) Innate lymphoid cells. Med Sci 33(5):534–542

    Google Scholar 

  51. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H (2013) Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 31:413–441

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. Simoni Y, Fehlings M, Kløverpris HN, McGovern N, Koo SL, Loh CY, Lim S, Kurioka A, Fergusson JR, Tang CL, Kam MH, Dennis K, Lim TKH, Fui ACY, Hoong CW, Chan JKY, Curotto de Lafaille M, Narayanan S, Baig S, Shabeer M, Toh SAES, Tan HKK, Anicete R, Tan EH, Takano A, Klenerman P, Leslie A, Tan DSW, Tan IB, Ginhoux F, Newell EW (2017) Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity 46(1):148–161

    PubMed  Article  CAS  Google Scholar 

  53. Wu N, Veillette A (2016) SLAM family receptors in normal immunity and immune pathologies. Curr Opin Immunol 38:45–51

    PubMed  Article  CAS  Google Scholar 

  54. Bryceson YT, Ljunggren HG, Long EO (2009) Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 114(13):2657–2666

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  55. Garg A, Barnes PF, Porgador A, Roy S, Wu S, Nanda JS, Griffith DE, Girard WM, Rawal N, Shetty S, Vankayalapati R (2006) Vimentin expressed on Mycobacterium tuberculosis-infected human monocytes is involved in binding to the NKp46 receptor. J Immunol 177(9):6192–6198

    PubMed  Article  CAS  Google Scholar 

  56. Narni-Mancinelli E, Gauthier L, Baratin M, Guia S, Fenis A, Deghmane AE, Rossi B, Fourquet P, Escalière B, Kerdiles YM, Ugolini S, Taha MK, Vivier E (2017) Complement factor P is a ligand for the natural killer cell-activating receptor NKp46. Sci Immunol 2(10):eaam9628

    PubMed  PubMed Central  Article  Google Scholar 

  57. Gur C, Enk J, Kassem SA, Suissa Y, Magenheim J, Stolovich-Rain M, Nir T, Achdout H, Glaser B, Shapiro J, Naparstek Y, Porgador A, Dor Y, Mandelboim O (2011) Recognition and killing of human and murine pancreatic beta cells by the NK receptor NKp46. J Immunol 187(6):3096–3103

    PubMed  Article  CAS  Google Scholar 

  58. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Münz C (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195(3):343–351

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  59. Bloushtain N, Qimron U, Bar-Ilan A, Hershkovitz O, Gazit R, Fima E, Korc M, Vlodavsky I, Bovin NV, Porgador A (2004) Membrane-associated heparan sulfate proteoglycans are involved in the recognition of cellular targets by NKp30 and NKp46. J Immunol 173(4):2392–2401

    PubMed  Article  CAS  Google Scholar 

  60. Hecht ML, Rosental B, Horlacher T, Hershkovitz O, de Paz JL, Noti C, Schauer S, Porgador A, Seeberger PH (2009) Natural cytotoxicity receptors NKp30, NKp44 and NKp46 bind to different heparan sulfate/heparin sequences. J Proteome Res 8(2):712–720

    PubMed  Article  CAS  Google Scholar 

  61. Hershkovitz O, Jarahian M, Zilka A, Bar-Ilan A, Landau G, Jivov S, Tekoah Y, Glicklis R, Gallagher JT, Hoffmann SC, Zer H, Mandelboim O, Watzl C, Momburg F, Porgador A (2008) Altered glycosylation of recombinant NKp30 hampers binding to heparan sulfate: a lesson for the use of recombinant immunoreceptors as an immunological tool. Glycobiology 18(1):28–41

    PubMed  Article  CAS  Google Scholar 

  62. Brusilovsky M, Radinsky O, Cohen L, Yossef R, Shemesh A, Braiman A, Mandelboim O, Campbell KS, Porgador A (2015) Regulation of natural cytotoxicity receptors by heparan sulfate proteoglycans in -cis: a lesson from NKp44. Eur J Immunol 45(4):1180–1191

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. Warren HS, Jones AL, Freeman C, Bettadapura J, Parish CR (2005) Evidence that the cellular ligand for the human NK cell activation receptor NKp30 is not a heparan sulfate glycosaminoglycan. J Immunol 175(1):207–212

    PubMed  Article  CAS  Google Scholar 

  64. Brandt CS, Baratin M, Yi EC, Kennedy J, Gao Z, Fox B, Haldeman B, Ostrander CD, Kaifu T, Chabannon C, Moretta A, West R, Xu WF, Vivier E, Levin SD (2009) The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med 206(7):1495–1503

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. Xu X, Li Y, Gauthier L, Chen Q, Vivier E, Mariuzza RA (2015) Expression, crystallization and X-ray diffraction analysis of a complex between B7-H6, a tumor cell ligand for the natural cytotoxicity receptor NKp30, and an inhibitory antibody. Acta Crystallogr F Struct Biol Commun 71(Pt 6):697–701

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. Hartmann J, Tran TV, Kaudeer J, Oberle K, Herrmann J, Quagliano I, Abel T, Cohnen A, Gatterdam V, Jacobs A, Wollscheid B, Tampé R, Watzl C, Diefenbach A, Koch J (2012) The stalk domain and the glycosylation status of the activating natural killer cell receptor NKp30 are important for ligand binding. J Biol Chem 287(37):31527–31539

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. Matta J, Baratin M, Chiche L, Forel JM, Cognet C, Thomas G, Farnarier C, Piperoglou C, Papazian L, Chaussabel D, Ugolini S, Vely F, Vivier E (2013) Induction of B7-H6, a ligand for the natural killer cell-activating receptor NKp30, in inflammatory conditions. Blood 122(3):394–404

    PubMed  Article  CAS  Google Scholar 

  68. Schlecker E, Fiegler N, Arnold A, Altevogt P, Rose-John S, Moldenhauer G, Sucker A, Paschen A, von Strandmann EP, Textor S, Cerwenka A (2014) Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30. Cancer Res 74(13):3429–3440

    PubMed  Article  CAS  Google Scholar 

  69. Pesce S, Tabellini G, Cantoni C, Patrizi O, Coltrini D, Rampinelli F, Matta J, Vivier E, Moretta A, Parolini S, Marcenaro E (2015) B7-H6-mediated downregulation of NKp30 in NK cells contributes to ovarian carcinoma immune escape. Oncoimmunology 4(4):e1001224

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Böll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A (2007) Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity 27(6):965–974

    PubMed  Article  CAS  Google Scholar 

  71. Wu W, Song W, Li S, Ouyang S, Fok KL, Diao R, Miao S, Chan HC, Wang L (2012) Regulation of apoptosis by Bat3-enhanced YWK-II/APLP2 protein stability. J Cell Sci 125(Pt 18):4219–4229

    PubMed  Article  CAS  Google Scholar 

  72. Rosental B, Brusilovsky M, Hadad U, Oz D, Appel MY, Afergan F, Yossef R, Rosenberg LA, Aharoni A, Cerwenka A, Campbell KS, Braiman A, Porgador A (2011) Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J Immunol 187(11):5693–5702

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. Horton NC, Mathew SO, Mathew PA (2013) Novel interaction between proliferating cell nuclear antigen and HLA I on the surface of tumor cells inhibits NK cell function through NKp44. PLoS One 8(3):e59552

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. Korgun ET, Celik-Ozenci C, Acar N, Cayli S, Desoye G, Demir R (2006) Location of cell cycle regulators cyclin B1, cyclin A, PCNA, Ki67 and cell cycle inhibitors p21, p27 and p57 in human first trimester placenta and deciduas. Histochem Cell Biol 125(6):615–624

    PubMed  Article  CAS  Google Scholar 

  75. Baychelier F, Sennepin A, Ermonval M, Dorgham K, Debre P, Vieillard V (2013) Identification of a cellular ligand for the natural cytotoxicity receptor NKp44. Blood 122(17):2935–2942

    PubMed  Article  CAS  Google Scholar 

  76. Vieillard V, Habib RE, Brochard P, Delache B, Bovendo HF, Calvo J, Morin J, Picq I, Martinon F, Vaslin B, le Grand R, Debré P (2008) CCR5 or CXCR4 use influences the relationship between CD4 cell depletion, NKp44L expression and NK cytotoxicity in SHIV-infected macaques. AIDS 22(2):185–192

    PubMed  Article  CAS  Google Scholar 

  77. Vieillard V, Strominger JL, Debre P (2005) NK cytotoxicity against CD4+ T cells during HIV-1 infection: a gp41 peptide induces the expression of an NKp44 ligand. Proc Natl Acad Sci U S A 102(31):10981–10986

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. Barrow AD et al. (2017) Natural killer cells control tumor growth by sensing a growth factor. Cell

  79. Akatsuka A, Ito M, Yamauchi C, Ochiai A, Yamamoto K, Matsumoto N (2010) Tumor cells of non-hematopoietic and hematopoietic origins express activation-induced C-type lectin, the ligand for killer cell lectin-like receptor F1. Int Immunol 22(9):783–790

    PubMed  Article  CAS  Google Scholar 

  80. Welte S, Kuttruff S, Waldhauer I, Steinle A (2006) Mutual activation of natural killer cells and monocytes mediated by NKp80-AICL interaction. Nat Immunol 7(12):1334–1342

    PubMed  Article  CAS  Google Scholar 

  81. Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44(5):989–1004

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. Casado JG, Pawelec G, Morgado S, Sanchez-Correa B, Delgado E, Gayoso I, Duran E, Solana R, Tarazona R (2009) Expression of adhesion molecules and ligands for activating and costimulatory receptors involved in cell-mediated cytotoxicity in a large panel of human melanoma cell lines. Cancer Immunol Immunother 58(9):1517–1526

    PubMed  Article  CAS  Google Scholar 

  83. 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 U S A 106(42):17858–17863

    PubMed  PubMed Central  Article  Google Scholar 

  84. Stengel KF, Harden-Bowles K, Yu X, Rouge L, Yin J, Comps-Agrar L, Wiesmann C, Bazan JF, Eaton DL, Grogan JL (2012) Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc Natl Acad Sci U S A 109(14):5399–5404

    PubMed  PubMed Central  Article  Google Scholar 

  85. Yu X, Harden K, C Gonzalez L, Francesco M, Chiang E, Irving B, Tom I, Ivelja S, Refino CJ, Clark H, Eaton D, Grogan JL (2009) The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10(1):48–57

    PubMed  Article  CAS  Google Scholar 

  86. Bernhardt G (2014) TACTILE becomes tangible: CD96 discloses its inhibitory peculiarities. Nat Immunol 15(5):406–408

    PubMed  Article  CAS  Google Scholar 

  87. Chan CJ, Martinet L, Gilfillan S, Souza-Fonseca-Guimaraes F, Chow MT, Town L, Ritchie DS, Colonna M, Andrews DM, Smyth MJ (2014) The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat Immunol 15(5):431–438

    PubMed  Article  CAS  Google Scholar 

  88. Xu F, Liu J, Liu D, Liu B, Wang M, Hu Z, du X, Tang L, He F (2014) LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res 74(13):3418–3428

    PubMed  Article  CAS  Google Scholar 

  89. Kouo T, Huang L, Pucsek AB, Cao M, Solt S, Armstrong T, Jaffee E (2015) Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res 3(4):412–423

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. Miyazaki T, Dierich A, Benoist C, Mathis D (1996) Independent modes of natural killing distinguished in mice lacking Lag3. Science 272(5260):405–408

    PubMed  Article  CAS  Google Scholar 

  91. Ndhlovu LC, Lopez-Verges S, Barbour JD, Jones RB, Jha AR, Long BR, Schoeffler EC, Fujita T, Nixon DF, Lanier LL (2012) Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 119(16):3734–3743

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. Ju Y, Hou N, Meng J, Wang X, Zhang X, Zhao D, Liu Y, Zhu F, Zhang L, Sun W, Liang X, Gao L, Ma C (2010) T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates natural killer cell suppression in chronic hepatitis B. J Hepatol 52(3):322–329

    PubMed  Article  CAS  Google Scholar 

  93. da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, Osman I, Bhardwaj N (2014) Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res 2(5):410–422

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. Xu L, Huang Y, Tan L, Yu W, Chen D, Lu CC, He J, Wu G, Liu X, Zhang Y (2015) Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. Int Immunopharmacol 29(2):635–641

    PubMed  Article  CAS  Google Scholar 

  95. Della Chiesa M et al (2016) Features of memory-like and PD-1(+) human NK cell subsets. Front Immunol 7:351

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. Pesce S et al (2017) Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol 139(1):335–346 e3

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  97. Boussiotis VA, Chatterjee P, Li L (2014) Biochemical signaling of PD-1 on T cells and its functional implications. Cancer J 20(4):265–271

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. Beldi-Ferchiou A, Lambert M, Dogniaux S, Vély F, Vivier E, Olive D, Dupuy S, Levasseur F, Zucman D, Lebbé C, Sène D, Hivroz C, Caillat-Zucman S (2016) PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget 7(45):72961–72977

    PubMed  PubMed Central  Article  Google Scholar 

  99. Taylor S, Huang Y, Mallett G, Stathopoulou C, Felizardo TC, Sun MA, Martin EL, Zhu N, Woodward EL, Elias MS, Scott J, Reynolds NJ, Paul WE, Fowler DH, Amarnath S (2017) PD-1 regulates KLRG1+ group 2 innate lymphoid cells. J Exp Med 214(6):1663–1678

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T (2013) A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 14(12):1212–1218

    PubMed  Article  CAS  Google Scholar 

  101. Mahoney KM, Freeman GJ, McDermott DF (2015) The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther 37(4):764–782

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. Huang Y, Guo L, Qiu J, Chen X, Hu-Li J, Siebenlist U, Williamson PR, Urban JF Jr, Paul WE (2015) IL-25-responsive, lineage-negative KLRG1(hi) cells are multipotential ‘inflammatory’ type 2 innate lymphoid cells. Nat Immunol 16(2):161–169

    PubMed  Article  CAS  Google Scholar 

  103. Ito M, Maruyama T, Saito N, Koganei S, Yamamoto K, Matsumoto N (2006) Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. J Exp Med 203(2):289–295

    PubMed  PubMed Central  Article  Google Scholar 

  104. Salimi M, Barlow JL, Saunders SP, Xue L, Gutowska-Owsiak D, Wang X, Huang LC, Johnson D, Scanlon ST, McKenzie ANJ, Fallon PG, Ogg GS (2013) A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med 210(13):2939–2950

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. Grundemann C, Bauer M, Schweier O, von Oppen N, Lassing U, Saudan P, Becker KF, Karp K, Hanke T, Bachmann MF, Pircher H (2006) Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1. J Immunol 176(3):1311–1315

    PubMed  Article  Google Scholar 

  106. Henson SM, Akbar AN (2009) KLRG1--more than a marker for T cell senescence. Age 31(4):285–291

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. Robbins SH, Nguyen KB, Takahashi N, Mikayama T, Biron CA, Brossay L (2002) Cutting edge: inhibitory functions of the killer cell lectin-like receptor G1 molecule during the activation of mouse NK cells. J Immunol 168(6):2585–2589

    PubMed  Article  CAS  Google Scholar 

  108. Schwartzkopff S, Grundemann C, Schweier O, Rosshart S, Karjalainen KE, Becker KF, Pircher H (2007) Tumor-associated E-cadherin mutations affect binding to the killer cell lectin-like receptor G1 in humans. J Immunol 179(2):1022–1029

    PubMed  Article  CAS  Google Scholar 

  109. Ryan JC, Seaman WE (1997) Divergent functions of lectin-like receptors on NK cells. Immunol Rev 155:79–89

    PubMed  Article  CAS  Google Scholar 

  110. Rosen DB, Bettadapura J, Alsharifi M, Mathew PA, Warren HS, Lanier LL (2005) Cutting edge: lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. J Immunol 175(12):7796–7799

    PubMed  Article  CAS  Google Scholar 

  111. Kirkham CL, Carlyle JR (2014) Complexity and diversity of the NKR-P1:Clr (Klrb1:Clec2) recognition systems. Front Immunol 5:214

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. Carlyle JR, Jamieson AM, Gasser S, Clingan CS, Arase H, Raulet DH (2004) Missing self-recognition of Ocil/Clr-b by inhibitory NKR-P1 natural killer cell receptors. Proc Natl Acad Sci U S A 101(10):3527–3532

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. Carlyle JR, Mesci A, Ljutic B, Belanger S, Tai LH, Rousselle E, Troke AD, Proteau MF, Makrigiannis AP (2006) Molecular and genetic basis for strain-dependent NK1.1 alloreactivity of mouse NK cells. J Immunol 176(12):7511–7524

    PubMed  Article  CAS  Google Scholar 

  114. Lanier LL, Chang C, Phillips JH (1994) Human NKR-P1A. A disulfide-linked homodimer of the C-type lectin superfamily expressed by a subset of NK and T lymphocytes. J Immunol 153(6):2417–2428

    PubMed  CAS  Google Scholar 

  115. 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(10):6508–6517

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  116. Rahim MM et al (2015) The mouse NKR-P1B:Clr-b recognition system is a negative regulator of innate immune responses. Blood 125(14):2217–2227

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. Pazina T et al (2017) Regulation of the functions of natural cytotoxicity receptors by interactions with diverse ligands and alterations in splice variant expression. Front Immunol 8:369

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. Ebbo M, Crinier A, Vély F, Vivier E (2017) Innate lymphoid cells: major players in inflammatory diseases. Nat Rev Immunol 17:665–678

    PubMed  Article  CAS  Google Scholar 

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Funding

This work was supported by a European Research Council advanced grant (TILC.), the Agence Nationale de la Recherche; Equipe Labellisée “La Ligue,” Ligue Nationale contre le Cancer, and institutional grants to the CIML (INSERM, CNRS, and Aix-Marseille University) and to Marseille Immunopôle.

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Author notes

  1. Sophie Guia and Aurore Fenis contributed equally to this work.

Affiliations

  1. Aix Marseille Univ, CNRS, INSERM, Centre d’Immunologie de Marseille-Luminy, Marseille, France

    Sophie Guia, Aurore Fenis, Eric Vivier & Emilie Narni-Mancinelli

  2. Innate Pharma Research Laboratories, Innate Pharma, Marseille, France

    Aurore Fenis & Eric Vivier

  3. Immunology, Marseille Immunopole, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille, Marseille, France

    Eric Vivier

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  1. Sophie Guia
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  2. Aurore Fenis
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  3. Eric Vivier
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  4. Emilie Narni-Mancinelli
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Correspondence to Emilie Narni-Mancinelli.

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E.V. is a cofounder and employee of Innate Pharma.

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This article is a contribution to the special issue on Innate Lymphoid Cells in Inflammation and Immunity - Guest Editors: Jan-Eric Turner and Georg Gasteiger

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Guia, S., Fenis, A., Vivier, E. et al. Activating and inhibitory receptors expressed on innate lymphoid cells. Semin Immunopathol 40, 331–341 (2018). https://doi.org/10.1007/s00281-018-0685-x

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  • DOI: https://doi.org/10.1007/s00281-018-0685-x

Keywords

  • ILC
  • NK cells
  • NCR
  • Checkpoints