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Cited by 175Cell Adhesion Molecules ResearchCellular Mechanics and InteractionsT-cell and B-cell Immunology

F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse

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Comrie, William A., Babich, Alexander, Burkhardt, Janis K.·2015·Journal of Cell Biology
DOI 10.1083/jcb.201406121PMC PMC4332248
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Abstract

Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. Regulation of integrin function occurs via conformational change, which modulates ligand affinity, and receptor clustering, which modulates valency. Here, we show that conformational intermediates of leukocyte functional antigen 1 (LFA-1) form a concentric array at the immunological synapse. Using an inhibitor cocktail to arrest F-actin dynamics, we show that organization of this array depends on F-actin flow and ligand mobility. Furthermore, F-actin flow is critical for maintaining the high affinity conformation of LFA-1, for increasing valency by recruiting LFA-1 to the immunological synapse, and ultimately for promoting intracellular cell adhesion molecule 1 (ICAM-1) binding. Finally, we show that F-actin forces are opposed by immobilized ICAM-1, which triggers LFA-1 activation through a combination of induced fit and tension-based mechanisms. Our data provide direct support for a model in which the T cell actin network generates mechanical forces that regulate LFA-1 activity at the immunological synapse.

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  • Tensile force generated by polarized F-actin polymerization allows for integrin activation and focal adhesion maturation, both of which are necessary for cellular adhesion and migration through extracellular matrices.

    “Tensile force generated by polarized F-actin polymerization allows for integrin activation and focal adhesion maturation, both of which are necessary for cellular adhesion and migration through extracellular matrices (Fig. 1b) [18, 19].”

    From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [19]

    The Introduction and Discussion report that force from centripetal F-actin flow promotes LFA-1 activation and T cell–APC adhesion at the immunological synapse. The paper does not establish that this force drives focal adhesion maturation or that those processes are necessary for migration through extracellular matrices. No page numbers are available in our copy. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Comrie, W. A., Babich, A., & Burkhardt, J. K.
Affiliations
Children's Hospital of Philadelphia (US)
Corresponding author
Burkhardt, Janis K.
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2015-02-09
Volume
208
Issue
4
Pages
475-491
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.201406121
PMC
PMC4332248
OpenAlex
W1976044471
Cited by
175
References
1
Citations by year
2026: 10 · 2025: 8 · 2024: 10 · 2023: 10 · 2022: 11 · 2021: 19 · 2020: 18 · 2019: 23 · 2018: 23 · 2017: 18 · 2016: 21 · 2015: 4
FWCI
17.65
Type
journal article
Language
en
Open access
Locations
  • The Journal of Cell Biology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Children's Hospital of Philadelphia
  • University of Pennsylvania
  • National Institutes of Health
  • National Cancer Institute (P30CA016520)
  • National Institute of General Medical Sciences (GM104867, R01GM104867)
  • National Institute of Allergy and Infectious Diseases (R01AI065644)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR007442)
Topics
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
LFA-1, immunological synapse, integrin conformational change, ICAM-1, T cell activation, receptor clustering, valence, induced fit, T cell adhesion, antigen-presenting cells
MeSH terms
Actins, B-Lymphocytes, Cell Communication, Cells, Cultured, Enzyme Activation, Humans, Lymphocyte Activation, Protein Binding, Signal Transduction, CD4-Positive T-Lymphocytes, Lymphocyte Function-Associated Antigen-1, Protein Structure, Tertiary, CD8-Positive T-Lymphocytes, Intercellular Adhesion Molecule-1, Integrin beta1, Myosin Type II, Immunological Synapses

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