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Cited by 142Immune Cell Function and InteractionImmune cells in cancerinterferon and immune responses

Phospholipase C-γ2 is essential for NK cell cytotoxicity and innate immunity to malignant and virally infected cells

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Caraux, Anouk, Kim, Nayoung, Bell, Sarah E., Zompi, Simona, Ranson, Thomas, Lesjean-Pottier, Sarah, Garcia-Ojeda, Marcos E., Turner, Martin +1 more·2006·Blood
DOI 10.1182/blood-2005-06-2428
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Abstract

Phospholipase C-γ2 (PLC-γ2) is a key component of signal transduction in leukocytes. In natural killer (NK) cells, PLC-γ2 is pivotal for cellular cytotoxicity; however, it is not known which steps of the cytolytic machinery it regulates. We found that PLC-γ2-deficient NK cells formed conjugates with target cells and polarized the microtubule-organizing center, but failed to secrete cytotoxic granules, due to defective calcium mobilization. Consequently, cytotoxicity was completely abrogated in PLC-γ2-deficient cells, regardless of whether targets expressed NKG2D ligands, missed self major histocompatibility complex (MHC) class I, or whether NK cells were stimulated with IL-2 and antibodies specific for NKR-P1C, CD16, CD244, Ly49D, and Ly49H. Defective secretion was specific to cytotoxic granules because release of IFN-γ on stimulation with IL-12 was normal. Plcg2-/- mice could not reject MHC class I-deficient lymphoma cells nor could they control CMV infection, but they effectively contained Listeria monocytogenes infection. Our results suggest that exocytosis of cytotoxic granules, but not cellular polarization toward targets, depends on intracellular calcium rise during NK cell cytotoxicity. In vivo, PLC-γ2 regulates selective facets of innate immunity because it is essential for NK cell responses to malignant and virally infected cells but not to bacterial infections.

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  • PLCγ2 is essential for murine NK cell cytotoxic function, as it is required for cytotoxic granule secretion and calcium flux.

    “Indeed, PLCγ2 is essential for murine NK cell cytotoxic function as it is required for cytotoxic granule secretion and calcium flux (94, 95).”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [95]

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Research works printed but not linked: 37

  1. Cerwenka A, Lanier LL. Natural killer cells, vi- ruses and cancer. Nat Rev Immunol. 2001;1:41- 49.
  2. Raulet DH. Interplay of natural killer cells and their receptors with the adaptive immune re- sponse. Nat Immunol. 2004;5:996-1002.
  3. Lanier LL. Natural killer cell receptor signaling. Curr Opin Immunol. 2003;15:308-314.
  4. Colucci F, Caligiuri MA, Di Santo JP. What does it take to make a natural killer? Nat Rev Immunol. 2003;3:413-425.
  5. Colucci F, Di Santo JP, Leibson PJ. Natural killer cell activation in mice and men: different triggers for similar weapons? Nat Immunol. 2002;3:807- 813.
  6. Lowin-Kropf B, Kunz B, Schneider P, Held W. A role for the src family kinase Fyn in NK cell activa- tion and the formation of the repertoire of Ly49 receptors. Eur J Immunol. 2002;32:773-782.
  7. Wen T, Zhang L, Kung SK, Molina TJ, Miller RG, Mak T. Alloskin graft rejection, tumor rejection and natural killer activity in mice lacking p56lck. Eur J Immunol. 1995;25:3155-3159.
  8. Colucci F, Schweighoffer E, Tomasello E, et al. Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases. Nat Immunol. 2002; 3:288-294.
  9. Colucci F, Rosmaraki E, Bregenholt S, et al. Functional dichotomy in natural killer cell signal- ing: Vav-1-dependent and -independent mecha- nisms. J Exp Med. 2001;193:1413-1424.
  10. Cella M, Fujikawa K, Tassi I, et al. Differential re- quirements for Vav proteins in DAP10-and ITAM- mediated NK cell cytotoxicity. J Exp Med. 2004; 200:817-823.
  11. Zhang W, Sommers CL, Burshtyn DN, et al. Es- sential role of LAT in T cell development. Immu- nity. 1999;10:323-332.
  12. Peterson EJ, Clements JL, Ballas ZK, Koretzky GA. NK cytokine secretion and cytotoxicity occur independently of the SLP-76 adaptor protein. Eur J Immunol. 1999;29:2223-2232.
  13. Billadeau DD, Brumbaugh KM, Dick CJ, Schoon RA, Bustelo XR, Leibson PJ. The Vav-Rac1 path- way in cytotoxic lymphocytes regulates the gen- eration of cell-mediated killing. J Exp Med. 1998; 188:549-559.
  14. Galandrini R, Palmieri G, Piccoli M, Frati L, San- toni A. Role for the Rac1 exchange factor Vav in the signaling pathways leading to NK cell cytotox- icity. J Immunol. 1999;162:3148-3152.
  15. Ji QS, Winnier GE, Niswender KD, et al. Essen- tial role of the tyrosine kinase substrate phospho- lipase C-gamma1 in mammalian growth and de- velopment. Proc Natl Acad Sci U S A. 1997;94: 2999-3003.
  16. Bell SE, Vigorito E, McAdam S, et al. PLCgamma2 regulates Bcl-2 levels and is required for survival rather than differentiation of marginal zone and follicular B cells. Eur J Immunol. 2004;34:2237- 2247.
  17. Ting AT, Karnitz LM, Schoon RA, Abraham RT, Leibson PJ. Fc gamma receptor activation in- duces the tyrosine phosphorylation of both phos- pholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells. J Exp Med. 1992;176:1751- 1755.
  18. Upshaw JL, Schoon, RA, Dick, JC, Billadeau, D, Leibson, PJ. The isoforms of phospholipase C-␥ are differentially used by distinct human NK acti- vating receptors. J Immunol. 2005;175:213-218.
  19. Colucci F, Soudais C, Rosmaraki E, Vanes L, Ty- bulewicz VL, Di Santo JP. Dissecting NK cell de- velopment using a novel alymphoid mouse model: investigating the role of the c-abl proto- oncogene in murine NK cell differentiation. J Im- munol. 1999;162:2761-2765.
  20. Penack O, Gentilini C, Fischer L, et al. CD56dim- CD16neg cells are responsible for natural cyto- toxicity against tumor targets. Leukemia 2005;19: 835-40.
  21. Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M. Sensitive and viable identification of antigen-specific CD8 ϩ T cells by a flow cytometry assay for degranulation. J Immu- nol Methods 2003;281:65-78.
  22. Bregenholt S, Berche P, Brombacher F, Di Santo JP. Conventional alpha beta T cells are sufficient for innate and adaptive immunity against enteric Listeria monocytogenes. J Immunol. 2001;166: 1871-1876.
  23. Depatie C, Muise E, Lepage P, Gros P, Vidal SM. High-resolution linkage map in the proximity of the host resistance locus Cmv1. Genomics. 1997; 39:154-163.
  24. Kupfer A, Singer SJ. Cell biology of cytotoxic and helper T cell functions: immunofluorescence mi- croscopic studies of single cells and cell couples. Annu Rev Immunol. 1989;7:309-337.
  25. Lyubchenko TA, Wurth GA, Zweifach A. Role of calcium influx in cytotoxic T lymphocyte lytic gran- ule exocytosis during target cell killing. Immunity. 2001;15:847-859.
  26. Toomey JA, Gays F, Foster D, Brooks CG. Cyto- kine requirements for the growth and develop- ment of mouse NK cells in vitro. J Leukoc Biol. 2003;74:233-242.
  27. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP. Natural killer cells in antiviral defense: function and regulation by innate cyto- kines. Annu Rev Immunol. 1999;17:189-220.
  28. Zompi S, Hamerman JA, Ogasawara K, et al. NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases. Nat Immu- nol. 2003;4:565-572.
  29. Dunn PL, North RJ. Early gamma interferon pro- duction by natural killer cells is important in de- fense against murine listeriosis. Infect Immun. 1991;59:2892-2900.
  30. Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Sci- ence. 2002;296:1323-1326.
  31. Smith HR, Heusel JW, Mehta IK, et al. Recogni- tion of a virus-encoded ligand by a natural killer cell activation receptor. Proc Natl Acad Sci U S A. 2002;99:8826-8831.
  32. Tay CH, Welsh RM. Distinct organ-dependent mechanisms for the control of murine cytomega- lovirus infection by natural killer cells. J Virol. 1997;71:267-275.
  33. Trinchieri G. The choices of a natural killer. Nat Immunol. 2003;4:509-510.
  34. Leibson PJ. Signal transduction during natural killer activation: inside the mind of a killer. Immu- nity. 1997;6:655-661.
  35. Herberman RB, Reynolds CW, Ortaldo JR. Mechanism of cytotoxicity by natural killer (NK) cells. Annu Rev Immunol. 1986;4:651-680.
  36. Griffiths GM, Argon Y. Structure and biogenesis of lytic granules. Curr Top Microbiol Immunol. 1995; 198:39-58.
  37. Jiang K, Zhong B, Gilvary DL, et al. Pivotal role of phosphoinositide-3 kinase in regulation of cyto- toxicity in natural killer cells. Nat Immunol. 2000; 1:419-425.

Cited by

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Authors
Caraux, A., Kim, N., Bell, S. E., Zompi, S., Ranson, T., Lesjean-Pottier, S., Garcia-Ojeda, M. E., Turner, M., & Colucci, F.
Affiliations
  • Babraham Institute (GB)
  • From the Cytokines and Lymphoid Development Unit, Institut Pasteur, Paris, France; and Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom.
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2006-02-01
Volume
107
Issue
3
Pages
994-1002
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2005-06-2428
OpenAlex
W1986290063
Cited by
142
References
4
Citations by year
2026: 5 · 2025: 8 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 15 · 2020: 3 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 9 · 2015: 5 · 2014: 9 · 2013: 4 · 2012: 7
FWCI
2.93
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
Funders
Biotechnology and Biological Sciences Research Council (BBS/E/B/0000C212)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
PLCγ2, natural killer cells, NK cell cytotoxicity, calcium mobilization, NKG2D ligands, innate immunity, cytomegalovirus infection, Listeria monocytogenes
MeSH terms
Animals, Cytomegalovirus Infections, Immunity, Cellular, Immunity, Innate, Interferon-gamma, Killer Cells, Natural, Listeriosis, Lymphoma, Mice, Inbred BALB C, Receptors, Immunologic, Histocompatibility Antigens Class I, Antigens, CD, Mice, Knockout, Interleukin-12, Calcium Signaling, Microtubule-Organizing Center, Cell Line, Tumor, Mice, Phospholipase C gamma, Receptors, Natural Killer Cell, NK Cell Lectin-Like Receptor Subfamily K

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