Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity

Mitchell S. Wang, Yuesong Hu, Elisa E. Sanchez, Xihe Xie, Nathan H. Roy, Miguel Jesus, Benjamin Y. Winer, Elizabeth A. Zale, Weiyang Jin, Chirag Sachar, Joanne H. Lee, Yeonsun Hong, Minsoo Kim, Lance C. Kam, Khalid Salaita and Morgan Huse ()
Additional contact information
Mitchell S. Wang: Immunology Program, Memorial Sloan Kettering Cancer Center
Yuesong Hu: Emory University
Elisa E. Sanchez: Immunology Program, Memorial Sloan Kettering Cancer Center
Xihe Xie: Neuroscience Program, Weill-Cornell Graduate School of Medical Sciences
Nathan H. Roy: State University of New York Upstate Medical University
Miguel Jesus: Immunology Program, Memorial Sloan Kettering Cancer Center
Benjamin Y. Winer: Immunology Program, Memorial Sloan Kettering Cancer Center
Elizabeth A. Zale: Immunology Program, Memorial Sloan Kettering Cancer Center
Weiyang Jin: Columbia University
Chirag Sachar: Columbia University
Joanne H. Lee: Columbia University
Yeonsun Hong: University of Rochester Medical Center
Minsoo Kim: University of Rochester Medical Center
Lance C. Kam: Columbia University
Khalid Salaita: Emory University
Morgan Huse: Immunology Program, Memorial Sloan Kettering Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Cytotoxic lymphocytes fight pathogens and cancer by forming immune synapses with infected or transformed target cells and then secreting cytotoxic perforin and granzyme into the synaptic space, with potent and specific killing achieved by this focused delivery. The mechanisms that establish the precise location of secretory events, however, remain poorly understood. Here we use single cell biophysical measurements, micropatterning, and functional assays to demonstrate that localized mechanotransduction helps define the position of secretory events within the synapse. Ligand-bound integrins, predominantly the αLβ2 isoform LFA-1, function as spatial cues to attract lytic granules containing perforin and granzyme and induce their fusion with the plasma membrane for content release. LFA-1 is subjected to pulling forces within secretory domains, and disruption of these forces via depletion of the adaptor molecule talin abrogates cytotoxicity. We thus conclude that lymphocytes employ an integrin-dependent mechanical checkpoint to enhance their cytotoxic power and fidelity.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-30809-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30809-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-30809-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().