Abstract
Cytotoxic T lymphocytes (CTLs) fight intracellular pathogens and cancer by identifying and destroying infected or transformed target cells1. To kill, CTLs form a specialized cytotoxic immune synapse (IS) with a target of interest and then release toxic perforin and granzymes into the interface to elicit programmed cell death2,3,4,5. The IS then dissolves, enabling CTLs to search for additional prey and professional phagocytes to clear the corpse6. While the mechanisms governing IS assembly have been studied extensively, far less is known about target cell release. Here, we applied time-lapse imaging to explore the basis for IS dissolution and found that it occurred concomitantly with the cytoskeletal contraction of apoptotic targets. Genetic and pharmacological perturbation of this contraction response indicated that it was both necessary and sufficient for CTL dissociation. We also found that mechanical amplification of apoptotic contractility promoted faster CTL detachment and serial killing. Collectively, these results establish a biophysical basis for IS dissolution and highlight the importance of mechanosensory feedback in the regulation of cell–cell interactions.
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Data availability
Source data are provided with this paper. Original imaging data are available from the lead contact (husem@mskcc.org) upon request.
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Acknowledgements
We thank C. Jeronimo and N. Lovinger for technical support; M. Tipping and the MSKCC Molecular Cytology Core Facility for assistance with imaging; and M. Overholtzer, M. Baylies and members of the M.H. laboratory for advice. This work was supported in part by the National Institutes of Health (grant no. R01-AI087644 to M.H. and E.E.S.; grant no. R21-AI169847 to M.H.; and grant no. P30-CA008748 to the MSKCC), the Canadian Institutes of Health Research (grant no. PJT-169125 to M.F.O.), the Canada Research Chairs Program (grant no. 950-231665 to M.F.O.), the Ludwig Foundation for Cancer Immunotherapy (to M.D.J.), the Schmidt Science Fellows Program (to B.Y.W.), the Cancer Research Institute (to B.Y.W.) and the Ludwig Institute for Cancer Research (to M.T.-L.).
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E.E.S., M.T.-L., M.D.J., B.Y.W., S.B. and M.H. designed the experiments. E.E.S., M.T.-L., A.J.G., Y.A.E., E.C. and E.R. collected the data. E.E.S., A.J.G., G.A.-B. and M.H. analyzed the data. S.B., T.K., J.D., N.T., G.A.-B. and M.F.O. contributed key reagents and methods. E.E.S. and M.H. wrote the paper.
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Extended data
Extended Data Fig. 1 Apoptotic contraction predicts CTL dissociation in 3D culture.
Collagen gels containing CTV-labeled OT-1 CTLs and OVA-loaded, YFP+ B16F10 cells were imaged in the presence of PI together with either 100 µm zVAD or vehicle control (DMSO), as indicated. (a) Diagram schematizing the approach. (b) Time-lapse montage of a representative control contact, with conjugate formation indicated by the magenta asterisk, dissociation by the magenta arrowhead, and PI influx by the red asterisk. Time in H:MM is shown in the top left corner of each image. Scale bars = 20 µm. (c) Quantification of the time delay between the onset of contraction and target cell release (left) and between PI influx and target cell release (right). Violins encompass the entire distribution, dashed lines denote median, and dotted lines indicate upper and lower quartiles. Sample size is shown in parentheses at the top of each column. All P-values were calculated by unpaired, two-tailed Student’s t-test. Data are representative of two independent experiments.
Extended Data Fig. 2 Apoptotic contraction predicts CTL dissociation from multiple target cell types.
CTV-labeled OT-1 CTLs were imaged together with the indicated OVA-loaded target cells in the presence of both CellEvent Caspase 3/7 and PI. Left, time-lapse montages of representative contacts. Conjugate formation is indicated by magenta asterisks, dissociation by magenta arrowheads, CellEvent Caspase 3/7 flux by green asterisks, and PI influx by red asterisks. Time in H:MM is shown in the top left or right corner of each image. Scale bars = 20 µm. Right, quantification of offset time between contraction (Contract.), CellEvent Caspase 3/7 flux (Casp. 3/7), or PI flux and target cell release. Offset times to the left of the origin denote detachment before the index of interest, whereas offset times to the right of the origin denote detachment after. Violins encompass the entire distribution, dashed lines denote median, and dotted lines indicate upper and lower quartiles. Sample size is shown in parentheses for each row. P-values were calculated by one-way ANOVA with Tukey correction. ** and **** denote P = 0.0038 and P ≤ 0.0001, respectively. Data are representative of two independent experiments.
Extended Data Fig. 3 Apoptotic contraction correlates with NK cell dissociation.
CTV-labeled, primary murine NK cells were imaged together with B16F10 target cells in the presence of both CellEvent Caspase 3/7 and PI. (a) A time-lapse montage of a representative contact is shown below, with schematic diagrams above. Dissociation is indicated by the cyan arrowhead. Time in H:MM is shown in the top right corner of each image. Scale bars = 20 µm. (b) Quantification of offset time between contraction (Contract.), CellEvent Caspase 3/7 flux (Casp. 3/7), or PI flux and target cell release. Offset times to the left of the origin denote detachment before the index of interest, whereas offset times to the right of the origin denote detachment after. Violins encompass the entire distribution, dashed lines denote median, and dotted lines indicate upper and lower quartiles. Sample size is shown in parentheses for each row. P-values were calculated by one-way ANOVA with Tukey correction. ***, ****, and ns denote P = 0.0008, P ≤ 0.0001, and P = 0.7269, respectively. Data are representative of two independent experiments.
Extended Data Fig. 4 CTL dissociation is not intrinsic to the lytic IS.
CTV-labeled Prf1+/+ OT-1 CTLs and CellVue Maroon-labeled Prf1-/- OT-1 CTLs were imaged together with OVA-loaded, YFP+ B16F10 in the presence of PI. (a) A time-lapse montage of a representative ternary interaction is shown below, with schematic diagrams above. Dissociation and PI influx are indicated by the magenta arrowhead and red asterisk, respectively. Time in H:MM is shown in the top left corner of each image. Scale bars = 20 µm. (b) Quantification of IS duration for the indicated Prf1+/+ (WT) and Prf1-/- CTLs. (c) Quantification of the time delay between the onset of contraction and target cell release, for both Prf1+/+ (WT) and Prf1-/- CTLs involved in ternary complexes. In b and c, violins encompass the entire distribution, dashed lines denote median, and dotted lines indicate upper and lower quartiles. Sample size is shown in parentheses at the top of each column. P values calculated by one-way ANOVA with Tukey correction (b) or unpaired, two-tailed Student’s t-test (c). Data are representative of two independent experiments.
Extended Data Fig. 5 Structural characterization of apoptotic contraction.
(a) CTV-labeled OT-1 CTLs were imaged together with OVA-loaded MB49 cells expressing both Myl12b-GFP and Tractin-RFP. Mean fluorescence intensity of Myl12b-GFP and Tractin-RFP in five representative target cells is shown, graphed over time together with the length of the cell along its major axis. (b) CTV-labeled OT-1 CTLs were imaged with OVA-loaded MB49 cells. A time-lapse montage of a representative killing event is shown, with brightfield and fluorescence channels above and IRM below. Red arrows denote the footprint of the contracting target, which detaches completely from the substrate. Scale bars = 20 µm.
Extended Data Fig. 6 Cytoskeletal contraction is necessary for CTL dissociation.
(a-b) B16F10 cells were antigen-loaded in the indicated concentrations of OVA, pretreated with MycB or vehicle control (DMSO), and then cocultured with CTV-labeled Prf1+/+ (wild type, a) or Prf1-/- (b) OT-1 CTLs. After 4 h, intracellular IFNγ and TNF production was assessed by intracellular cytokine staining. Left, schematic diagrams indicating the anticipated architectural disposition of CTL-target cell conjugates. Center, anticipated target cell stiffness and contact duration are indicated. Right, intracellular IFNγ and TNF production, graphed as the percentage of cytokine+ CTLs. Bars denote mean values from technical triplicate measurements, which are shown as circles. (c-e) B16F10 cells expressing Cherry alone (Ctrl) or DeAct together with Cherry (DeAct) were loaded with OVA and imaged with CTV-labelled CTLs in the presence of CellEvent Caspase 3/7. (c) Time-lapse montages of representative contacts are shown to the right, with schematic diagrams to the left. Conjugate formation is indicated by magenta asterisks, dissociation by magenta arrowheads, and CellEvent Caspase 3/7 flux by green asterisks. Time in H:MM is shown in the top left corner of each image. Scale bars = 20 µm. (d) Quantification of the time delay between CellEvent Caspase 3/7 flux and target cell release. (e) 2D plot relating the starting area of the indicated target cells to the time interval between CellEvent Caspase 3/7 flux and target cell release. (f) The time interval between the start and end of contraction, measured in B16F10 cells engaged by OT-1 CTLs in the presence of 100 µm zVAD-FMK (zVAD) or vehicle control (DMSO). (g) The time interval between the start and end of contraction, measured for wild type (WT) and Rock1nc MEFs engaged by OT-1 CTLs. Sample size is shown in parentheses at the top of each column in d, f, and g. Violins encompass the entire distribution, dashed lines denote median, and dotted lines indicate upper and lower quartiles. P-values were calculated by two-tailed unpaired Student’s t test. All data are representative of at least two independent experiments.
Extended Data Fig. 7 Calculation of Ca2+ decay indices.
Diagrams schematizing the calculation of Ca2+ decay indices for the contraction (a) and release (b) phases of the cytolytic response. Left, for each wild type response, indices are calculated by dividing the mean Fura-2 ratio during the contraction or release phase by the mean Fura-2 ratio during the engagement phase. Then, reference indices (right) are calculated by applying the same contraction, release, and engagement intervals to a collection of reference Ca2+ responses taken from synaptically engaged Prf1-/- CTLs. This results in a paired set of ‘wild type’ and ‘Prf1-/- ref’ values (center).
Extended Data Fig. 8 Substrate stiffness controls target cell morphology and CTL dissociation.
B16F10 cells were cultured on hydrogels of varying stiffness (4-50 kPa) or glass. (a) Representative images of phalloidin stained cells cultured on the indicated surfaces. Scale bars = 20 µm. (b) Quantification of target cell area on the indicated substrates. (c) CTV-labeled OT-1 CTLs were imaged in the presence of PI together with OVA-loaded B16F10 cells on hydrogels of varying stiffness or glass. Graph shows quantification of the time delay between PI influx and target cell release. Sample size is shown in parentheses at the top of each column in b and c. Violins encompass the entire distribution, dashed lines denote median, and dotted lines indicate upper and lower quartiles. P-values were calculated by one-way ANOVA with Tukey correction. Data are representative of two independent experiments.
Extended Data Fig. 9 Model for CTL dissociation.
Apoptotic contraction promotes CTL detachment by attenuating activating signals. Timely target cell release facilitates both serial killing by the CTL and corpse clearance by patrolling phagocytes.
Supplementary information
Supplementary Information
Legends for Supplementary Videos 1–17 and Supplementary Figure showing the gating strategy for the cytokine production experiments.
Supplementary Video 1
WT (Prf1+/+) CTLs kill and dissociate from target cells. CTV-labeled Prf1+/+ OT-1 CTLs (cyan) were imaged together with OVA-loaded YFP+ B16-F10 cells (yellow) in the presence of PI (red). A representative 600× time-lapse video is shown. Time in HH:MM is shown in the upper left corner.
Supplementary Video 2
Prf1−/− CTLs neither kill nor dissociate from target cells. CTV-labeled Prf1−/− OT-1 CTLs (cyan) were imaged together with OVA-loaded YFP+ B16-F10 cells (yellow) in the presence of PI. A representative 600× time-lapse video is shown. Time in HH:MM is shown in the upper left corner.
Supplementary Video 3
CTL dissociation is tightly correlated with apoptotic contraction. CTV-labeled OT-1 CTLs (cyan) were imaged together with OVA-loaded B16-F10 cells in the presence of both CellEvent Caspase-3/7 green (green) and PI (red). A representative 600× time-lapse video is shown. Fluorescence signals have been overlaid onto the brightfield images. Time in HH:MM is shown in the upper right corner.
Supplementary Video 4
CTL dissociation correlates with apoptotic contraction in 3D culture. CTV-labeled OT-1 CTLs (cyan) and OVA-loaded YFP+ B16-F10 cells (yellow) were embedded in collagen and then imaged in the presence of PI (red). A representative 1,500× time-lapse video is shown. Fluorescence signals have been overlaid onto the brightfield images. Time in HH:MM is shown in the upper left corner.
Supplementary Video 5
Contraction-induced dissociation is not specific to the lytic IS. CTV-labeled WT (Prf1+/+) OT-1 CTLs (cyan) and CellVue maroon-labeled Prf1−/− OT-1 CTLs (white) were mixed and then imaged together with OVA-loaded YFP+ B16-F10 cells (yellow) in the presence of PI (red). A representative 600× time-lapse video is shown. Time in HH:MM is shown in the lower left corner.
Supplementary Video 6
Actomyosin cables accumulate in contracting target cells. MB49 target cells expressing Myl12b–GFP (white) and tractin–RFP (red) were OVA-loaded and then imaged by confocal microscopy together with CTV-labeled OT-1 CTLs (cyan). A representative 385× time-lapse video is shown. Time in H:MM:SS.SSS is shown in the lower right corner.
Supplementary Video 7
CTL dissociation from targets under control conditions. OVA-loaded B16-F10 cells were pretreated with vehicle (DMSO) and then imaged together with CTV-labeled OT-1 CTLs (cyan) in the presence of both CellEvent Caspase-3/7 green (green) and PI (red). A representative 600× time-lapse video is shown. Fluorescence signals have been overlaid onto the brightfield images. Time in HH:MM is shown in the upper left corner. This control response is included for comparison with the MycB condition (Supplementary Video 8).
Supplementary Video 8
Depletion of target cell F-actin inhibits CTL dissociation. OVA-loaded B16-F10 cells were pretreated with MycB and then imaged together with CTV-labeled OT-1 CTLs (cyan) in the presence of both CellEvent Caspase 3/7 green (green) and PI (red). A representative 600× time-lapse video is shown. Fluorescence signals have been overlaid onto the brightfield images. Time in HH:MM is shown in the upper left corner.
Supplementary Video 9
CTL dissociation from targets under control conditions. B16-F10 cells expressing control Cherry vector (red) were OVA-loaded and then imaged together with CTV-labeled OT-1 CTLs (cyan) in the presence of CellEvent Caspase 3/7 green (green). A representative 600× time-lapse video is shown. Time in HH:MM is shown in the upper left corner. This control response is included for comparison with the DeAct condition (Supplementary Video 10).
Supplementary Video 10
Depletion of target cell F-actin inhibits CTL dissociation. B16-F10 cells expressing DeAct and Cherry (red) were OVA-loaded and then imaged together with CTV-labeled OT-1 CTLs (cyan) in the presence of CellEvent Caspase 3/7 green (green). A representative 600× time-lapse video is shown. Time in HH:MM is shown in the upper left corner.
Supplementary Video 11
CTL dissociation from targets under control conditions. OVA-loaded YFP+ B16-F10 cells (yellow) were pretreated with vehicle (DMSO) and then imaged together with CTV-labeled OT-1 CTLs (cyan) in the presence of PI (red). A representative 960× time-lapse video is shown. Time in HH:MM is shown in the upper left corner. This control response is included for comparison with the zVAD condition (Supplementary Video 12).
Supplementary Video 12
Caspase inhibition delays CTL dissociation. OVA-loaded YFP+ B16-F10 cells (yellow) were pretreated with zVAD and then imaged together with CTV-labeled OT-1 CTLs (cyan) in the presence of zVAD and PI (red). A representative 960× time-lapse video is shown. Time in HH:MM is shown in the upper left corner.
Supplementary Video 13
CTL dissociation from targets under control conditions. OVA-loaded MEFs were imaged together with CTV-labeled OT-1 CTLs (cyan) in the presence of PI (red). A representative 1,200× time-lapse video is shown. Fluorescence signals have been overlaid onto the brightfield images. Time in HH:MM is shown in the upper left corner. This control response is included for comparison with the Rock1nc condition (Supplementary Video 14).
Supplementary Video 14
Rock1 cleavage promotes target cell contraction and CTL dissociation. OVA-loaded Rock1nc MEFs were imaged together with CTV-labeled OT-1 CTLs (cyan) in the presence of PI (red). A representative 1,200× time-lapse video is shown. Fluorescence signals have been overlaid onto the brightfield images. Time in HH:MM is shown in the upper left corner.
Supplementary Video 15
Reduced CTL Ca2+ signaling precedes dissociation. OT-1 CTLs were loaded with Fura-2AM and then imaged together with OVA-loaded B16-F10 cells. A representative 600× time-lapse video is shown. The Fura-2AM ratio is depicted in pseudocolor with cold and warm colors indicating low and high intracellular Ca2+, respectively. Fura-2AM signals have been overlaid onto the brightfield images. Time in HH:MM is shown in the upper left corner.
Supplementary Video 16
Cytoskeletal contraction is sufficient to induce CTL dissociation. MB49 cells expressing GFP–Rock2–ER (green) were OVA-loaded and then imaged together with CTV-labeled Prf1−/− OT-1 CTLs (cyan). A representative 600× time-lapse video is shown. Fluorescence signals have been overlaid onto the brightfield images. Time in HH:MM is shown in the upper right corner. 4-OHT was added to the cells at the 35-min time point to induce GFP–Rock2–ER dimerization and activation.
Supplementary Video 17
GFP–ER induces neither target contraction nor CTL dissociation. MB49 cells expressing GFP–ER (green) were OVA-loaded and then imaged together with CTV-labeled Prf1−/− OT-1 CTLs (cyan). A representative 600× time-lapse video is shown. Fluorescence signals have been overlaid onto the brightfield images. Time in HH:MM is shown in the lower left corner. 4-OHT was added to the cells at the 40-min time point to induce GFP–ER dimerization.
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Sanchez, E.E., Tello-Lafoz, M., Guo, A.J. et al. Apoptotic contraction drives target cell release by cytotoxic T cells. Nat Immunol 24, 1434–1442 (2023). https://doi.org/10.1038/s41590-023-01572-4
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DOI: https://doi.org/10.1038/s41590-023-01572-4
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