Apoptotic contraction drives target cell release by cytotoxic T cells

Sanchez, Elisa E.; Tello-Lafoz, María; Guo, Aixuan J.; Jesús, Miguel de; Elbanna, Yassmin A.; Winer, Benjamin Y.; Budhu, Sadna; Chan, Eric Chun Yong; Rosiek, Eric; Kondo, Taisuke; DuSold, Justyn; Taylor, Naomi; Altan‐Bonnet, Grégoire; Olson, Michael F.; Huse, Morgan

doi:10.1038/s41590-023-01572-4

Cited by 10 publications

(7 citation statements)

References 35 publications

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“…To determine whether CTLs form analogously shaped contacts with target cells, we imaged conjugates of perforin deficient ( Prf1 −/− ) OT-1 CTLs and antigen-loaded B16 melanoma cells by confocal microscopy. Prf1 −/− CTLs were used to prevent the rapid cytoskeletal contraction and synapse dissolution induced by target cell apoptosis ( 32 ). The synapses that we observed were both dynamic and highly protrusive (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity

de Jesus,

Settle,

Vorselen

et al. 2024

Sci. Immunol.

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Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.

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Section: Resultsmentioning

confidence: 99%

Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity

de Jesus,

Settle,

Vorselen

et al. 2024

Sci. Immunol.

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“…Once the target cell starts to die or commences apoptosis, its cytoskeleton undergoes what is called apoptotic contraction. The killer cell senses what is going on through the immunological synapse, and consequently it breaks its connection with the target cell, releasing the dying cell so that the killer can go on to target other cells in what is known as serial killing [ 216 , 217 ].…”

Section: How Nk Cells and Cytotoxic T Cells Recognize And Eliminate V...mentioning

confidence: 99%

“…These stages of the cytotoxic process are elegantly discussed in articles by Paul and Lai [ 23 ] and Sanchez et al [ 216 , 217 ].…”

Section: How Nk Cells and Cytotoxic T Cells Recognize And Eliminate V...mentioning

confidence: 99%

“…releasing the dying cell so that the killer can go on to target other cells in what is known as serial killing [216,217].…”

Section: Stage 4-post-apoptosis Detachment Of the Killer Cellmentioning

confidence: 99%

“…These stages of the cytotoxic process are elegantly discussed in articles by Paul and Lai [23] and Sanchez et al [216,217]. 3) In viral-infected and cancer cells, MHC Class I is significantly reduced, preventing the inhibitory receptor from engaging with it.…”

Section: Stage 4-post-apoptosis Detachment Of the Killer Cellmentioning

confidence: 99%

See 2 more Smart Citations

Natural Killer Cells and Cytotoxic T Cells: Complementary Partners against Microorganisms and Cancer

Vojdani,

Koksoy,

Vojdani

et al. 2024

Microorganisms

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Natural killer (NK) cells and cytotoxic T (CD8+) cells are two of the most important types of immune cells in our body, protecting it from deadly invaders. While the NK cell is part of the innate immune system, the CD8+ cell is one of the major components of adaptive immunity. Still, these two very different types of cells share the most important function of destroying pathogen-infected and tumorous cells by releasing cytotoxic granules that promote proteolytic cleavage of harmful cells, leading to apoptosis. In this review, we look not only at NK and CD8+ T cells but also pay particular attention to their different subpopulations, the immune defenders that include the CD56+CD16dim, CD56dimCD16+, CD57+, and CD57+CD16+ NK cells, the NKT, CD57+CD8+, and KIR+CD8+ T cells, and ILCs. We examine all these cells in relation to their role in the protection of the body against different microorganisms and cancer, with an emphasis on their mechanisms and their clinical importance. Overall, close collaboration between NK cells and CD8+ T cells may play an important role in immune function and disease pathogenesis. The knowledge of how these immune cells interact in defending the body against pathogens and cancers may help us find ways to optimize their defensive and healing capabilities with methods that can be clinically applied.

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PIEZO1‐mediated mechanosensing governs NK‐cell killing efficiency and infiltration in three‐dimensional matrices

Yanamandra,

Zhang,

Montalvo

et al. 2024

Eur J Immunol

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Natural killer (NK) cells play a vital role in eliminating tumorigenic cells. Efficient locating and killing of target cells in complex three‐dimensional (3D) environments are critical for their functions under physiological conditions. However, the role of mechanosensing in regulating NK‐cell killing efficiency in physiologically relevant scenarios is poorly understood. Here, we report that the responsiveness of NK cells is regulated by tumor cell stiffness. NK‐cell killing efficiency in 3D is impaired against softened tumor cells, whereas it is enhanced against stiffened tumor cells. Notably, the durations required for NK‐cell killing and detachment are significantly shortened for stiffened tumor cells. Furthermore, we have identified PIEZO1 as the predominantly expressed mechanosensitive ion channel among the examined candidates in NK cells. Perturbation of PIEZO1 abolishes stiffness‐dependent NK‐cell responsiveness, significantly impairs the killing efficiency of NK cells in 3D, and substantially reduces NK‐cell infiltration into 3D collagen matrices. Conversely, PIEZO1 activation enhances NK killing efficiency as well as infiltration. In conclusion, our findings demonstrate that PIEZO1‐mediated mechanosensing is crucial for NK killing functions, highlighting the role of mechanosensing in NK‐cell killing efficiency under 3D physiological conditions and the influence of environmental physical cues on NK‐cell functions.

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Apoptotic contraction drives target cell release by cytotoxic T cells

Cited by 10 publications

References 35 publications

Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity

Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity

Natural Killer Cells and Cytotoxic T Cells: Complementary Partners against Microorganisms and Cancer

PIEZO1‐mediated mechanosensing governs NK‐cell killing efficiency and infiltration in three‐dimensional matrices

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