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Title: Interfacial actin protrusions mechanically enhance killing by cytotoxic T cells

Abstract

Cytotoxic T lymphocytes (CTLs) kill by forming immunological synapses with target cells and secreting toxic proteases and the pore-forming protein perforin into the intercellular space. Immunological synapses are highly dynamic structures that boost perforin activity by applying mechanical force against the target cell. Here, we used high-resolution imaging and microfabrication to investigate how CTLs exert synaptic forces and coordinate their mechanical output with perforin secretion. Using micropatterned stimulatory substrates that enable synapse growth in three dimensions, we found that perforin release occurs at the base of actin-rich protrusions that extend from central and intermediate locations within the synapse. These protrusions, which depended on the cytoskeletal regulator WASP and the Arp2/3 actin nucleation complex, were required for synaptic force exertion and efficient killing. They also mediated physical deformation of the target cell surface during CTL–target cell interactions. Here our results reveal the mechanical basis of cellular cytotoxicity and highlight the functional importance of dynamic, three-dimensional architecture in immune cell-cell interfaces.

Authors:
ORCiD logo [1]; ORCiD logo [2]; ORCiD logo [3]; ORCiD logo [1];  [1]; ORCiD logo [4]; ORCiD logo [5]; ORCiD logo [3]; ORCiD logo [1]
  1. Memorial Sloan Kettering Cancer Center, New York, NY (United States)
  2. Weill Cornell Medical College, New York, NY (United States)
  3. Columbia Univ., New York, NY (United States)
  4. Howard Hughes Medical Institute, Ashburn, VA (United States)
  5. Brookhaven National Lab. (BNL), Upton, NY (United States)
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1508745
Report Number(s):
BNL-211580-2019-JAAM
Journal ID: ISSN 2470-9468
Grant/Contract Number:  
SC0012704
Resource Type:
Accepted Manuscript
Journal Name:
Science Immunology
Additional Journal Information:
Journal Volume: 4; Journal Issue: 33; Journal ID: ISSN 2470-9468
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE

Citation Formats

Tamzalit, Fella, Wang, Mitchell S., Jin, Weiyang, Tello-Lafoz, Maria, Boyko, Vitaly, Heddleston, John M., Black, Charles T., Kam, Lance C., and Huse, Morgan. Interfacial actin protrusions mechanically enhance killing by cytotoxic T cells. United States: N. p., 2019. Web. doi:10.1126/sciimmunol.aav5445.
Tamzalit, Fella, Wang, Mitchell S., Jin, Weiyang, Tello-Lafoz, Maria, Boyko, Vitaly, Heddleston, John M., Black, Charles T., Kam, Lance C., & Huse, Morgan. Interfacial actin protrusions mechanically enhance killing by cytotoxic T cells. United States. doi:10.1126/sciimmunol.aav5445.
Tamzalit, Fella, Wang, Mitchell S., Jin, Weiyang, Tello-Lafoz, Maria, Boyko, Vitaly, Heddleston, John M., Black, Charles T., Kam, Lance C., and Huse, Morgan. Fri . "Interfacial actin protrusions mechanically enhance killing by cytotoxic T cells". United States. doi:10.1126/sciimmunol.aav5445.
@article{osti_1508745,
title = {Interfacial actin protrusions mechanically enhance killing by cytotoxic T cells},
author = {Tamzalit, Fella and Wang, Mitchell S. and Jin, Weiyang and Tello-Lafoz, Maria and Boyko, Vitaly and Heddleston, John M. and Black, Charles T. and Kam, Lance C. and Huse, Morgan},
abstractNote = {Cytotoxic T lymphocytes (CTLs) kill by forming immunological synapses with target cells and secreting toxic proteases and the pore-forming protein perforin into the intercellular space. Immunological synapses are highly dynamic structures that boost perforin activity by applying mechanical force against the target cell. Here, we used high-resolution imaging and microfabrication to investigate how CTLs exert synaptic forces and coordinate their mechanical output with perforin secretion. Using micropatterned stimulatory substrates that enable synapse growth in three dimensions, we found that perforin release occurs at the base of actin-rich protrusions that extend from central and intermediate locations within the synapse. These protrusions, which depended on the cytoskeletal regulator WASP and the Arp2/3 actin nucleation complex, were required for synaptic force exertion and efficient killing. They also mediated physical deformation of the target cell surface during CTL–target cell interactions. Here our results reveal the mechanical basis of cellular cytotoxicity and highlight the functional importance of dynamic, three-dimensional architecture in immune cell-cell interfaces.},
doi = {10.1126/sciimmunol.aav5445},
journal = {Science Immunology},
number = 33,
volume = 4,
place = {United States},
year = {2019},
month = {3}
}

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This content will become publicly available on March 22, 2020
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