Immunologic Research

, Volume 43, Issue 1–3, pp 210–222 | Cite as

Endocytosis as a mechanism of regulating natural killer cell function: unique endocytic and trafficking pathway for CD94/NKG2A

  • Giovanna Peruzzi
  • Madhan Masilamani
  • Francisco Borrego
  • John E. Coligan
Article

Abstract

Natural killer (NK) cells are lymphocytes generally recognized as sentinels of the innate immune system due to their inherent capacity to deal with diseased (stressed) cells, including malignant and infected. This ability to recognize many potentially pathogenic situations is due to the expression of a diverse panel of activation receptors. Because NK cell activation triggers an aggressive inflammatory response, it is important to have a means of throttling this response. Hence, NK cells also express a panel of inhibitory receptors that recognize ligands expressed by “normal” cells. Little or nothing is known about the endocytosis and trafficking of NK cell receptors, which are of great relevance to understanding how NK cells maintain the appropriate balance of activating and inhibitory receptors on their cell surface. In this review, we focus on the ITIM-containing inhibitory receptor CD94/NKG2A showing that it is endocytosed by a previously undescribed macropinocytic-like process that may be related to the maintenance of its surface expression.

Keywords

NK cells Inhibitory/activating receptors Endocytosis Trafficking CD94/NKG2A 

Notes

Acknowledgment

This work was supported by the intramural program of the NIAID/NIH.

References

  1. 1.
    Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187–376.PubMedCrossRefGoogle Scholar
  2. 2.
    Moretta L, Biassoni R, Bottino C, Cantoni C, Pende D, Mingari MC, et al. Human NK cells and their receptors. Microbes Infect. 2002;4:1539–44.PubMedCrossRefGoogle Scholar
  3. 3.
    Hallett WH, Murphy WJ. Positive and negative regulation of natural killer cells: therapeutic implications. Semin Cancer Biol. 2006;16:367–82.PubMedCrossRefGoogle Scholar
  4. 4.
    Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008;9:495–502.PubMedCrossRefGoogle Scholar
  5. 5.
    Maxfield FR, McGraw TE. Endocytic recycling. Nat Rev Mol Cell Biol. 2004;5:121–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Masilamani M, Narayanan S, Prieto M, Borrego F, Coligan JE. Uncommon endocytic and trafficking pathway of the natural killer cell CD94/NKG2A inhibitory receptor. Traffic. 2008;9:1019–34.PubMedCrossRefGoogle Scholar
  7. 7.
    Reth M. Antigen receptor tail clue. Nature. 1989;338:383–4.PubMedCrossRefGoogle Scholar
  8. 8.
    McVicar DW, Taylor LS, Gosselin P, Willette-Brown J, Mikhael AI, Geahlen RL, et al. DAP12-mediated signal transduction in natural killer cells. A dominant role for the Syk protein-tyrosine kinase. J Biol Chem. 1998;273:32934–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Billadeau DD, Upshaw JL, Schoon RA, Dick CJ, Leibson PJ. NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nat Immunol. 2003;4:557–64.PubMedCrossRefGoogle Scholar
  10. 10.
    Bryceson YT, March ME, Ljunggren HG, Long EO. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood. 2006;107:159–66.PubMedCrossRefGoogle Scholar
  11. 11.
    Hazenbos WL, Gessner JE, Hofhuis FM, Kuipers H, Meyer D, Heijnen IA, et al. Impaired IgG-dependent anaphylaxis and arthus reaction in Fc gamma RIII (CD16) deficient mice. Immunity. 1996;5:181–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Daeron M, Jaeger S, Du Pasquier L, Vivier M. Immunoreceptor tyrosine-based inhition motifs: a quest in the past and future. Immunol Rev. 2008;244:11–43.CrossRefGoogle Scholar
  13. 13.
    Kabat J, Borrego F, Brooks A, Coligan JE. Role that each NKG2A immunoreceptor tyrosine-based inhibitory motif plays in mediating the human CD94/NKG2A inhibitory signal. J Immunol. 2002;169:1948–58.PubMedGoogle Scholar
  14. 14.
    Stebbins CC, Watzl C, Billadeau DD, Leibson PJ, Burshtyn DN, Long EO. Vav1 dephosphorylation by the tyrosine phosphatase SHP–1 as a mechanism for inhibition of cellular cytotoxicity. Mol Cell Biol. 2003;23:6291–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Yu MC, Su LL, Zou L, Liu Y, Wu N, Kong L, et al. An essential function for beta-arrestin 2 in the inhibitory signaling of natural killer cells. Nat Immunol. 2008;9:898–907.PubMedCrossRefGoogle Scholar
  16. 16.
    Alvarez-Arias DA, Campbell KS. Protein kinase C regulates expression and function of inhibitory killer cell Ig-like receptors in NK cells. J Immunol. 2007;179:5281–90.PubMedGoogle Scholar
  17. 17.
    Borrego F, Kabat J, Kim DK, Lieto L, Maasho K, Pena J, et al. Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. Mol Immunol. 2002;38:637–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG. Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J Exp Med. 1998;187:813–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Benmerah A, Lamaze C. Clathrin-coated pits: vive la difference? Traffic. 2007;8:970–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Gong Q, Huntsman C, Ma D. Clathrin-independent internalization and recycling. J Cell Mol Med. 2008;12:126–44.PubMedCrossRefGoogle Scholar
  21. 21.
    Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature. 2003;422:37–44.PubMedCrossRefGoogle Scholar
  22. 22.
    Sorkin A. Cargo recognition during clathrin-mediated endocytosis: a team effort. Curr Opin Cell Biol. 2004;16:392–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Bonifacino JS, Traub LM. Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem. 2003;72:395–447.PubMedCrossRefGoogle Scholar
  24. 24.
    Traub LM. Sorting it out: AP–2 and alternate clathrin adaptors in endocytic cargo selection. J Cell Biol. 2003;163:203–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Jacquier V, Prummer M, Segura JM, Pick H, Vogel H. Visualizing odorant receptor trafficking in living cells down to the single-molecule level. Proc Natl Acad Sci U S A. 2006;103:14325–30.PubMedCrossRefGoogle Scholar
  26. 26.
    Blitzer JT, Nusse R. A critical role for endocytosis in Wnt signaling. BMC Cell Biol. 2006;7:28.PubMedCrossRefGoogle Scholar
  27. 27.
    Fattakhova G, Masilamani M, Borrego F, Gilfillan AM, Metcalfe DD, Coligan JE. The high-affinity immunoglobulin-E receptor (FcepsilonRI) is endocytosed by an AP–2/clathrin-independent, dynamin-dependent mechanism. Traffic. 2006;7:673–85.PubMedCrossRefGoogle Scholar
  28. 28.
    Praefcke GJ, McMahon HT. The dynamin superfamily: universal membrane tubulation and fission molecules? Nat Rev Mol Cell Biol. 2004;5:133–47.PubMedCrossRefGoogle Scholar
  29. 29.
    Hinshaw JE. Dynamin and its role in membrane fission. Annu Rev Cell Dev Biol. 2000;16:483–519.PubMedCrossRefGoogle Scholar
  30. 30.
    Lamaze C, Dujeancourt A, Baba T, Lo CG, Benmerah A, Dautry-Varsat A. Interleukin 2 receptors and detergent-resistant membrane domains define a clathrin-independent endocytic pathway. Mol Cell. 2001;7:661–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Sauvonnet N, Dujeancourt A, Dautry-Varsat A. Cortactin and dynamin are required for the clathrin-independent endocytosis of gammac cytokine receptor. J Cell Biol. 2005;168:155–63.PubMedCrossRefGoogle Scholar
  32. 32.
    Gold ES, Underhill DM, Morrissette NS, Guo J, McNiven MA, Aderem A. Dynamin 2 is required for phagocytosis in macrophages. J Exp Med. 1999;190:1849–56.PubMedCrossRefGoogle Scholar
  33. 33.
    Naslavsky N, Weigert R, Donaldson JG. Convergence of non-clathrin- and clathrin-derived endosomes involves Arf6 inactivation and changes in phosphoinositides. Mol Biol Cell. 2003;14:417–31.PubMedCrossRefGoogle Scholar
  34. 34.
    Naslavsky N, Weigert R, Donaldson JG. Characterization of a nonclathrin endocytic pathway: membrane cargo and lipid requirements. Mol Biol Cell. 2004;15:3542–52.PubMedCrossRefGoogle Scholar
  35. 35.
    Fourgeaud L, Bessis AS, Rossignol F, Pin JP, Olivo-Marin JC, Hemar A. The metabotropic glutamate receptor mGluR5 is endocytosed by a clathrin-independent pathway. J Biol Chem. 2003;278:12222–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Le Roy C, Wrana JL. Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nat Rev Mol Cell Biol. 2005;6:112–26.PubMedCrossRefGoogle Scholar
  37. 37.
    Nichols B. Caveosomes and endocytosis of lipid rafts. J Cell Sci. 2003;116:4707–14.PubMedCrossRefGoogle Scholar
  38. 38.
    Sato SB, Ishii K, Makino A, Iwabuchi K, Yamaji-Hasegawa A, Senoh Y, et al. Distribution and transport of cholesterol-rich membrane domains monitored by a membrane-impermeant fluorescent polyethylene glycol-derivatized cholesterol. J Biol Chem. 2004;279:23790–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Cuitino L, Matute R, Retamal C, Bu G, Inestrosa NC, Marzolo MP. ApoER2 is endocytosed by a clathrin-mediated process involving the adaptor protein Dab2 independent of its rafts’ association. Traffic. 2005;6:820–38.PubMedCrossRefGoogle Scholar
  40. 40.
    Laude AJ, Prior IA. Plasma membrane microdomains: organization, function and trafficking. Mol Membr Biol. 2004;21:193–205.PubMedCrossRefGoogle Scholar
  41. 41.
    Parton RG, Simons K. The multiple faces of caveolae. Nat Rev Mol Cell Biol. 2007;8:185–94.PubMedCrossRefGoogle Scholar
  42. 42.
    Nichols BJ, Kenworthy AK, Polishchuk RS, Lodge R, Roberts TH, Hirschberg K, et al. Rapid cycling of lipid raft markers between the cell surface and golgi complex. J Cell Biol. 2001;153:529–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Glebov OO, Bright NA, Nichols BJ. Flotillin–1 defines a clathrin-independent endocytic pathway in mammalian cells. Nat Cell Biol. 2006;8:46–54.PubMedCrossRefGoogle Scholar
  44. 44.
    Payne CK, Jones SA, Chen C, Zhuang X. Internalization and trafficking of cell surface proteoglycans and proteoglycan-binding ligands. Traffic. 2007;8:389–401.PubMedCrossRefGoogle Scholar
  45. 45.
    Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin–1 gene-disrupted mice. Science. 2001;293:2449–52.PubMedCrossRefGoogle Scholar
  46. 46.
    Oh P, McIntosh DP, Schnitzer JE. Dynamin at the neck of caveolae mediates their budding to form transport vesicles by GTP-driven fission from the plasma membrane of endothelium. J Cell Biol. 1998;141:101–14.PubMedCrossRefGoogle Scholar
  47. 47.
    Pelkmans L, Burli T, Zerial M, Helenius A. Caveolin-stabilized membrane domains as multifunctional transport and sorting devices in endocytic membrane traffic. Cell. 2004;118:767–80.PubMedCrossRefGoogle Scholar
  48. 48.
    Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL. Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol. 2003;5:410–21.PubMedCrossRefGoogle Scholar
  49. 49.
    Chadda R, Howes MT, Plowman SJ, Hancock JF, Parton RG, Mayor S. Cholesterol-sensitive Cdc42 activation regulates actin polymerization for endocytosis via the GEEC pathway. Traffic. 2007;8:702–17.PubMedCrossRefGoogle Scholar
  50. 50.
    Gauthier NC, Monzo P, Kaddai V, Doye A, Ricci V, Boquet P. Helicobacter pylori VacA cytotoxin. A probe for a clathrin-independent and Cdc42-dependent pinocytic pathway routed to late endosomes. Mol Biol Cell. 2005;16:4852–66.PubMedCrossRefGoogle Scholar
  51. 51.
    Kirkham M, Fujita A, Chadda R, Nixon SJ, Kurzchalia TV, Sharma DK, et al. Ultrastructural identification of uncoated caveolin-independent early endocytic vehicles. J Cell Biol. 2005;168:465–76.PubMedCrossRefGoogle Scholar
  52. 52.
    Sabharanjak S, Sharma P, Parton RG, Mayor S. GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway. Dev Cell. 2002;2:411–23.PubMedCrossRefGoogle Scholar
  53. 53.
    Putnam MA, Moquin AE, Merrihew M, Outcalt C, Sorge E, Caballero A, et al. Lipid raft-independent B cell receptor-mediated antigen internalization and intracellular trafficking. J Immunol. 2003;170:905–12.PubMedGoogle Scholar
  54. 54.
    Stoddart A, Jackson AP, Brodsky FM. Plasticity of B cell receptor internalization upon conditional depletion of clathrin. Mol Biol Cell. 2005;16:2339–48.PubMedCrossRefGoogle Scholar
  55. 55.
    Wilson BS, Steinberg SL, Liederman K, Pfeiffer JR, Surviladze Z, Zhang J, et al. Markers for detergent-resistant lipid rafts occupy distinct and dynamic domains in native membranes. Mol Biol Cell. 2004;15:2580–92.PubMedCrossRefGoogle Scholar
  56. 56.
    Swanson JA, Watts C. Macropinocytosis. Trends Cell Biol. 1995;5:424–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Jones AT. Macropinocytosis: searching for an endocytic identity and role in the uptake of cell penetrating peptides. J Cell Mol Med. 2007;11:670–84.PubMedCrossRefGoogle Scholar
  58. 58.
    Amyere M, Mettlen M, Van Der Smissen P, Platek A, Payrastre B, Veithen A, et al. Origin, originality, functions, subversions and molecular signalling of macropinocytosis. Int J Med Microbiol. 2002;291:487–94.PubMedCrossRefGoogle Scholar
  59. 59.
    Brown FD, Rozelle AL, Yin HL, Balla T, Donaldson JG. Phosphatidylinositol 4, 5-bisphosphate and Arf6-regulated membrane traffic. J Cell Biol. 2001;154:1007–17.PubMedCrossRefGoogle Scholar
  60. 60.
    Radhakrishna H, Donaldson JG. ADP-ribosylation factor 6 regulates a novel plasma membrane recycling pathway. J Cell Biol. 1997;139:49–61.PubMedCrossRefGoogle Scholar
  61. 61.
    Ridley AJ. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 2006;16:522–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Lindmo K, Stenmark H. Regulation of membrane traffic by phosphoinositide 3-kinases. J Cell Sci. 2006;119:605–14.PubMedCrossRefGoogle Scholar
  63. 63.
    Muro S, Wiewrodt R, Thomas A, Koniaris L, Albelda SM, Muzykantov VR, et al. A novel endocytic pathway induced by clustering endothelial ICAM–1 or PECAM-1. J Cell Sci. 2003;116:1599–609.PubMedCrossRefGoogle Scholar
  64. 64.
    West MA, Bretscher MS, Watts C. Distinct endocytotic pathways in epidermal growth factor-stimulated human carcinoma A431 cells. J Cell Biol. 1989;109:2731–9.PubMedCrossRefGoogle Scholar
  65. 65.
    von Delwig A, Hilkens CM, Altmann DM, Holmdahl R, Isaacs JD, Harding CV, et al. Inhibition of macropinocytosis blocks antigen presentation of type II collagen in vitro and in vivo in HLA-DR1 transgenic mice. Arthritis Res Ther. 2006;8:R93.CrossRefGoogle Scholar
  66. 66.
    Araki N, Johnson MT, Swanson JA. A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages. J Cell Biol. 1996;135:1249–60.PubMedCrossRefGoogle Scholar
  67. 67.
    Liu YC, Penninger J, Karin M. Immunity by ubiquitylation: a reversible process of modification. Nat Rev Immunol. 2005;5:941–52.PubMedCrossRefGoogle Scholar
  68. 68.
    Haglund K, Dikic I. Ubiquitylation and cell signaling. EMBO J. 2005;24:3353–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Mukhopadhyay D, Riezman H. Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science. 2007;315:201–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, et al. Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci U S A. 2005;102:2760–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Chen H, De Camilli P. The association of epsin with ubiquitinated cargo along the endocytic pathway is negatively regulated by its interaction with clathrin. Proc Natl Acad Sci U S A. 2005;102:2766–71.PubMedCrossRefGoogle Scholar
  72. 72.
    Mayor S, Pagano RE. Pathways of clathrin-independent endocytosis. Nat Rev Mol Cell Biol. 2007;8:603–12.PubMedCrossRefGoogle Scholar
  73. 73.
    Gruenberg J, Stenmark H. The biogenesis of multivesicular endosomes. Nat Rev Mol Cell Biol. 2004;5:317–23.PubMedCrossRefGoogle Scholar
  74. 74.
    Zerial M, McBride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol. 2001;2:107–17.PubMedCrossRefGoogle Scholar
  75. 75.
    Sonnichsen B, De Renzis S, Nielsen E, Rietdorf J, Zerial M. Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab11. J Cell Biol. 2000;149:901–14.PubMedCrossRefGoogle Scholar
  76. 76.
    Belleudi F, Leone L, Nobili V, Raffa S, Francescangeli F, Maggio M, et al. Keratinocyte growth factor receptor ligands target the receptor to different intracellular pathways. Traffic. 2007;8:1854–72.PubMedCrossRefGoogle Scholar
  77. 77.
    Elsasser S, Finley D. Delivery of ubiquitinated substrates to protein-unfolding machines. Nat Cell Biol. 2005;7:742–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Brooks AG, Posch PE, Scorzelli CJ, Borrego F, Coligan JE. NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J Exp Med. 1997;185:795–800.PubMedCrossRefGoogle Scholar
  79. 79.
    Borrego F, Masilamani M, Kabat J, Sanni TB, Coligan JE. The cell biology of the human natural killer cell CD94/NKG2A inhibitory receptor. Mol Immunol. 2005;42:485–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Borrego F, Masilamani M, Marusina AI, Tang X, Coligan JE. The CD94/NKG2 family of receptors from molecules and cells to clinical relevance. Immunol Res. 2006;35:263–78.PubMedCrossRefGoogle Scholar
  81. 81.
    Sanni TB, Masilamani M, Kabat J, Coligan JE, Borrego F. Exclusion of lipid rafts and decreased mobility of CD94/NKG2A receptors at the inhibitory NK cell synapse. Mol Biol Cell. 2004;15:3210–23.PubMedCrossRefGoogle Scholar
  82. 82.
    Masilamani M, Nguyen C, Kabat J, Borrego F, Coligan JE. CD94/NKG2A inhibits NK cell activation by disrupting the actin network at the immunological synapse. J Immunol. 2006;177:3590–6.PubMedGoogle Scholar
  83. 83.
    Borrego F, Kabat J, Sanni TB, Coligan JE. NK cell CD94/NKG2A inhibitory receptors are internalized and recycle independently of inhibitory signaling processes. J Immunol. 2002;169:6102–11.PubMedGoogle Scholar
  84. 84.
    Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature. 2002;419:734–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Lee JC, Lee KM, Kim DW, Heo DS. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 2004;172:7335–40.PubMedGoogle Scholar
  86. 86.
    Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z. Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol. 2008;180:7249–58.PubMedGoogle Scholar
  87. 87.
    Ogasawara K, Hamerman JA, Hsin H, Chikuma S, Bour-Jordan H, Chen T, et al. Impairment of NK cell function by NKG2D modulation in NOD mice. Immunity. 2003;18:41–51.PubMedCrossRefGoogle Scholar
  88. 88.
    Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 1992;70:401–10.PubMedCrossRefGoogle Scholar
  89. 89.
    Meyaard L. The inhibitory collagen receptor LAIR–1 (CD305). J Leukoc Biol. 2008;83:799–803.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • Giovanna Peruzzi
    • 1
  • Madhan Masilamani
    • 2
  • Francisco Borrego
    • 1
  • John E. Coligan
    • 1
  1. 1.Receptor Cell Biology Section, Laboratory of ImmunogeneticsNational Institute of Allergy and Infectious Diseases, NIHRockvilleUSA
  2. 2.Division of Pediatric Allergy and Immunology, Department of PediatricsMount Sinai School of MedicineNew YorkUSA

Personalised recommendations