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Published on: June 30, 2022
Cutting Edge: Murine NK Cells Degranulate and Retain Cytotoxic Function without Store-Operated Calcium Entry
Jacquelyn Freund-Brown1, Ruth Choa1, Brenal K Singh1
1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Abstract:
Sustained Ca2+ signaling, known as store-operated calcium entry (SOCE), occurs downstream of immunoreceptor engagement and is critical for cytotoxic lymphocyte signaling and effector function. CD8+ T cells require sustained Ca2+ signaling for inflammatory cytokine production and the killing of target cells; however, much less is known about its role in NK cells. In this study, we use mice deficient in stromal interacting molecules 1 and 2, which are required for SOCE, to examine the contribution of sustained Ca2+ signaling to murine NK cell function. Surprisingly, we found that, although SOCE is required for NK cell IFN-γ production in an NFAT-dependent manner, NK cell degranulation/cytotoxicity and tumor rejection in vivo remained intact in the absence of sustained Ca2+ signaling. Our data suggest that mouse NK cells use different signaling mechanisms for cytotoxicity compared with other cytotoxic lymphocytes.
Insights
Store-operated calcium entry (SOCE) is vital for T cell function but not NK cell cytotoxicity. Mice lacking SOCE showed intact NK cell degranulation and tumor rejection, suggesting distinct NK cell signaling pathways.
Area of Science:
- Immunology
- Cellular Signaling
- Calcium Signaling
Background:
- Sustained calcium (Ca2+) signaling, or store-operated calcium entry (SOCE), is crucial for cytotoxic lymphocyte function.
- While essential for CD8+ T cells, the role of SOCE in Natural Killer (NK) cell function is less understood.
Purpose of the Study:
- To investigate the contribution of sustained Ca2+ signaling (SOCE) to murine NK cell function.
- To determine if SOCE is required for NK cell effector functions like cytotoxicity and cytokine production.
Main Methods:
- Utilized mice deficient in stromal interacting molecules 1 and 2, which are essential for SOCE.
- Assessed NK cell IFN-γ production, degranulation, cytotoxicity, and in vivo tumor rejection.
Main Results:
- NK cell IFN-γ production was dependent on SOCE and NFAT signaling.
- Surprisingly, NK cell degranulation, cytotoxicity, and in vivo tumor rejection were unaffected in mice lacking SOCE.
- These findings indicate that NK cells do not rely on SOCE for cytotoxic effector functions.
Conclusions:
- Murine NK cells utilize distinct signaling mechanisms for cytotoxicity compared to other cytotoxic lymphocytes.
- Sustained Ca2+ signaling is dispensable for NK cell-mediated cytotoxicity and tumor surveillance.
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