Cutting Edge: Murine NK Cells Degranulate and Retain Cytotoxic Function without Store-Operated Calcium Entry

Freund-Brown, Jacquelyn; Choa, Ruth; Singh, Brenal K.; Robertson, Tanner F.; Ferry, Gabrielle M.; Viver, E.; Bassiri, Hamid; Burkhardt, Janis K.; Kambayashi, Taku

doi:10.4049/jimmunol.1700340

Cited by 12 publications

(9 citation statements)

References 29 publications

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“…In addition, there was a synchronized upregulation of well-characterized IFN-inducible genes, such as Irf9, Mx1 , and Isg20 . During the subsequent d2 to d4 transition, additional pathways included transcription factor NFAT signaling, which has been implicated in mediating NK cell production of IFN-γ 12–14 , as well as transcription factor ATF2–AP-1 signaling and T cell-related signaling (Fig. 2d).…”

Section: Resultsmentioning

confidence: 99%

Epigenetic control of innate and adaptive immune memory

et al. 2018

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Clonal expansion and immunological memory are hallmark features of the mammalian adaptive immune response and essential for prolonged host control of pathogens. Recent work demonstrates that natural killer (NK) cells of the innate immune system also exhibit these adaptive traits during infection. Here we demonstrate that differentiating and ‘memory’ NK cells possess distinct chromatin accessibility states and that their epigenetic profiles reveal a ‘poised’ regulatory program at the memory stage. Furthermore, we elucidate how individual STAT transcription factors differentially control epigenetic and transcriptional states early during infection. Finally, concurrent chromatin profiling of the canonical CD8+ T cell response against the same infection demonstrated parallel and distinct epigenetic signatures defining NK cells and CD8+ T cells. Overall, our study reveals the dynamic nature of epigenetic modifications during the generation of innate and adaptive lymphocyte memory.

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Section: Resultsmentioning

confidence: 99%

Epigenetic control of innate and adaptive immune memory

et al. 2018

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“…In murine NK cells, it was recently reported that degranulation was persisting in the complete absence of Ca 2+ (Freund‐Brown et al . ). This finding was based on in vivo data in STIM1/2 double knock‐out NK cells and on in vitro data in the absence of [Ca 2+ ] o .…”

Section: Discussionmentioning

confidence: 97%

“…While the importance of Orai1/CRAC channel activity for cytolytic immune cell functions has been convincingly demonstrated (Lyubchenko et al 2001;Maul-Pavicic et al 2011;Schwarz et al 2013;Klemann et al 2017), there are several reports that cytotoxicity is only slightly reduced in tumour-specific murine CTLs following a drastic reduction of Ca 2+ signals by the application of 1 μM BTP2 , one of the most potent CRAC channel blockers (Zitt et al 2004). In murine NK cells, it was recently reported that degranulation was persisting in the complete absence of Ca 2+ (Freund-Brown et al 2017). This finding was based on in vivo data in STIM1/2 double knock-out NK cells and on in vitro data in the absence of [Ca 2+ ] o .…”

Section: Discussionmentioning

confidence: 99%

“…FBS in our experiments added a large amount of Ca 2+ and we therefore chose to leave it out. In the experimental set-up used by (Freund-Brown et al 2017), FBS was added together with 250 μM EGTA to Ca 2+ -free medium (S-MEM). Depending on the Ca 2+ concentration in FBS, 250 μM may not be sufficient to reduce [Ca 2+ ] o to very low micromolar levels.…”

Section: Discussionmentioning

confidence: 99%

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A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity

Zhou

Friedmann

Lyrmann

et al. 2018

The Journal of Physiology

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Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells are required to protect the human body against cancer. Ca is a key metabolic factor for lymphocyte function and cancer homeostasis. We analysed the Ca dependence of CTL and NK cell cytotoxicity against cancer cells and found that CTLs have a bell-shaped Ca dependence with an optimum for cancer cell elimination at rather low [Ca ] (23-625 μm) and [Ca ] (122-334 nm). This finding predicts that a partial inhibition of Orai1 should increase (rather than decrease) cytotoxicity of CTLs at [Ca ] higher than 625 μm. We tested this hypothesis in CTLs and indeed found that partial down-regulation of Orai1 by siRNA increases the efficiency of cancer cell killing. We found two mechanisms that may account for the Ca optimum of cancer cell killing: (1) migration velocity and persistence have a moderate optimum between 500 and 1000 μm [Ca ] in CTLs, and (2) lytic granule release at the immune synapse between CTLs and cancer cells is increased at 146 μm compared to 3 or 800 μm, compatible with the Ca optimum for cancer cell killing. It has been demonstrated in many cancer cell types that Orai1-dependent Ca signals enhance proliferation. We propose that a decrease of [Ca ] or partial inhibition of Orai1 activity by selective blockers in the tumour microenvironment could efficiently reduce cancer growth by simultaneously increasing CTL and NK cell cytotoxicity and decreasing cancer cell proliferation.

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“…It is also possible that the discrepancies in question reflect species-specific effects; we used primary murine T cells while the previous study used human material [20]. Recently, it was shown that human, but not mouse, NK cells require Ca 2+ signaling for lytic granule exocytosis [30]. Hence, it is not implausible that synaptic F-actin dynamics might be governed by different signaling constraints in human than in mouse T cells.…”

Section: Discussionmentioning

confidence: 99%

Actin clearance promotes polarized dynein accumulation at the immunological synapse

Sanchez

Liu

Huse

2018

Preprint

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Immunological synapse (IS) formation between a T cell and an antigen-presenting cell is accompanied by the reorientation of the T cell centrosome toward the interface. This polarization response is thought to enhance the specificity of T cell effector function by enabling the directional secretion of cytokines and cytotoxic factors toward the antigen-presenting cell.Centrosome reorientation is controlled by polarized signaling through diacylglycerol (DAG) and protein kinase C (PKC). This drives the recruitment of the motor protein dynein to the IS, where it pulls on microtubules to reorient the centrosome. Here, we used T cell receptor photoactivation and imaging methodology to investigate the mechanisms controlling dynein accumulation at the synapse. Our results revealed a remarkable spatiotemporal correlation between dynein recruitment to the synaptic membrane and the depletion of cortical filamentous actin (F-actin) from the same region, suggesting that the two events were causally related.Consistent with this hypothesis, we found that pharmacological disruption of F-actin dynamics in T cells impaired both dynein accumulation and centrosome reorientation. DAG and PKC signaling were necessary for synaptic F-actin clearance and dynein accumulation, while calcium signaling and microtubules were dispensable for both responses. Taken together, these data provide mechanistic insight into the polarization of cytoskeletal regulators and highlight the close coordination between microtubule and F-actin architecture at the IS.

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Cutting Edge: Murine NK Cells Degranulate and Retain Cytotoxic Function without Store-Operated Calcium Entry

Cited by 12 publications

References 29 publications

Epigenetic control of innate and adaptive immune memory

Epigenetic control of innate and adaptive immune memory

A calcium optimum for cytotoxic T lymphocyte and natural killer cell cytotoxicity

Actin clearance promotes polarized dynein accumulation at the immunological synapse

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