Phospholipase C-γ2 Is a Critical Signaling Mediator for Murine NK Cell Activating Receptors
Open accessAbstract
Phospholipase C-γ (PLCγ) is a key regulator of intracellular Ca2+ mobilization. Two isoforms of PLCγ have been identified, PLCγ1 and PLCγ2. Previously, in vitro studies indicated that activating NK cell receptors signal through both isoforms. However, PLCγ2 deficiency alone was sufficient to induce a substantial impairment of NK cell-mediated cytotoxicity in vitro. Why PLCγ2 is more important than PLCγ1 for NK cell activation and whether PLCγ2 is also critical for NK cell development, secretion of IFN-γ, and clearance of viral infections in vivo is not known. In this study, we report that PLCγ2 is the predominant isoform expressed in murine NK cells. PLCγ2 deficiency did not affect NK cell numbers in bone marrow and spleen, but acquisition of Ly49 receptors by NK cells was partially impaired. PLCγ2-deficient NK cells exhibited a dramatic impairment of cytolytic function and IFN-γ production upon ligation of activating receptors, whereas they did secrete IFN-γ in response to cytokines. Consequently, mice lacking PLCγ2 controlled murine CMV infection substantially less effectively than did wild-type animals, and this defect was most evident in the spleen, where viral clearance mostly depends on NK cell lytic function. These results demonstrate that PLCγ2 is crucial for development of the NK cell receptor repertoire and signaling of activating NK cell receptors, mediating optimal NK cell function in vivo.
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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 [94]
The cytotoxicity results and Discussion report dramatically impaired murine NK-cell killing without PLCγ2, and the Discussion says PLCγ2 is required for intracellular calcium signaling (page numbers unavailable). The paper links calcium to lytic-granule exocytosis, but does not directly show that PLCγ2 is required for granule secretion; it also allows for PLCγ2-independent exocytosis pathways. (LLM, conf=0.83)
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- Authors
- Tassi, I., Presti, R., Kim, S., Yokoyama, W. M., Gilfillan, S., & Colonna, M.
- Affiliations
- Washington University in St. Louis (US)
- Howard Hughes Medical Institute (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-07
- Volume
- 175
- Issue
- 2
- Pages
- 749-754
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2107922203
- Cited by
- 121
- References
- 47
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 2 · 2016: 10 · 2015: 6 · 2014: 8 · 2013: 7 · 2012: 6
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI056139)
- National Center for Research Resources (C06RR012466)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- PLCγ2, PLCγ1, natural killer cells, Ly49 receptors, calcium mobilization, NK cell cytotoxicity, IFN-gamma production, viral clearance, NK cell development, receptor signaling
- MeSH terms
- Animals, Antigens, Ly, Cells, Cultured, Cytotoxicity, Immunologic, Cricetinae, Herpesviridae Infections, Interferon-gamma, Isoenzymes, Killer Cells, Natural, Lymphocyte Activation, Membrane Proteins, Mice, Inbred C57BL, Type C Phospholipases, Receptors, Immunologic, Signal Transduction, CHO Cells, Receptors, IgG, Muromegalovirus, Mice, Knockout, Lectins, C-Type, Adaptor Proteins, Signal Transducing, Mice, Phospholipase C gamma, Receptors, NK Cell Lectin-Like
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