Cortical actin recovery at the immunological synapse leads to termination of lytic granule secretion in cytotoxic T lymphocytes
Open accessAbstract
Significance: Cytotoxic T lymphocytes (CTLs) destroy virally infected and tumor cells through the directed secretion of specialized lysosomes called “lytic granules.” Because a single CTL must direct its cytotoxic activities only against specific targets but can sequentially kill multiple cells, granule secretion must be tightly controlled. We demonstrate here that dynamic regulation of the cortical actin cytoskeleton is critical for both the initiation and termination of secretion. We further link actin dynamics with phosphatidylinositol 4,5-bisphosphate (PIP 2 ) levels and provide evidence that lytic granule delivery initiates cortical actin recovery and the cessation of secretion. Our results suggest that actin both regulates and is regulated by secretion, providing a mechanism by which CTLs control their ability to kill targets serially during immune responses.
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ARP2/3-mediated actin polymerization drives cell spreading at immunological synapses and shapes the complex architectures that enable efficient antigen presentation and lymphocyte activation.
“ARP2/3-mediated actin polymerization drives cell spreading at immunological synapses and shapes the complex architectures that enable efficient antigen presentation and lymphocyte activation (Fig. 1e) [12, 22, 23].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [12]
The Results section (page not available) describes a ring-like actin structure at the cytotoxic T-cell synapse, supporting a role for actin dynamics in synapse architecture. But the paper does not establish that ARP2/3-mediated polymerization drives cell spreading or that these structures enable efficient antigen presentation and lymphocyte activation. (LLM, conf=0.79)
Experimental — accuracy not yet measuredA dense ring of branched actin surrounds the cytosol, creating a barrier at the cell cortex that regulates vesicle secretion.
“Additionally, a dense ring of branched actin surrounds the cytosol, creating a barrier at the cell cortex that regulates vesicle secretion [11–13].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [12]
The introductory passage (page unavailable) describes a dense cortical actin meshwork that envelops the cytosol, and the Discussion says recovered cortical actin acts as a barrier to lytic granule secretion in cytotoxic T lymphocytes. Our copy does not establish that this actin is branched; it describes a meshwork rather than a ring. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMultiple investigations found elevated surface CD107a levels after CD8+ T cell degranulation and lower cortical actin thickness.
“Multiple investigations found elevated surface CD107a levels after CD8 + T cell degranulation and lower cortical actin thickness”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [12]
The paper’s ‘Cortical Actin Recovery Correlates with Lytic Granule Secretion’ section reports reduced cortical actin density before granule fusion, but says actin recovers after degranulation. It tracks secretion with LAMP1-EGFP rather than reporting elevated surface CD107a, and it does not measure actin thickness. The actin–secretion relationship is supported, but the marker, measurement, and implied post-degranulation timing are not. (LLM, conf=0.82)
Experimental — accuracy not yet measuredHEM1-deficient T cells fail to properly integrate antigen signals and fully activate because T cell immune synapses are highly dependent on ARP2/3-mediated F-actin polymerization.
“Because T cell immune synapses are highly dependent on ARP2/3-mediated F-actin polymerization [12, 22, 23, 37], HEM1-deficient T cells fail to properly integrate antigen signals and fully activate.”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [12]
The Discussion (page unavailable in our copy) links actin dynamics at cytotoxic T-cell synapses to TCR signaling and lytic-granule secretion, supporting the general importance of actin at the synapse. It does not identify ARP2/3-mediated F-actin polymerization as the mechanism on which synapses depend. The HEM1-deficiency conclusion follows the citations and is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredReduced integrity of the mechanical actin barrier facilitates vesicular hypersecretion.
“indicating that reduced integrity of the mechanical actin barrier facilitates vesicular hypersecretion [8, 10, 12, 33].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [12]
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Research works printed but not linked: 3
- Weiss A, Samelson LE (2003) T-lymphocyte activation. Fundamental Immunology, ed Paul WE (Lippincott-Raven, New York), pp 321-363.
- Balla T, Varnai P (2009) Visualization of cellular phosphoinositide pools with GFP- fused protein-domains. Curr Protoc Cell Biol Chapter 24:Unit 24.4.
- Patterson GH, Lippincott-Schwartz J (2002) A photoactivatable GFP for selective photolabeling of proteins and cells. Science 297:1873-1877.
Cited by
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Yanamandra, A. K., Zhang, J., Montalvo, G., Zhou, X., Biedenweg, D., Zhao, R., Sharma, S., Hoth, M., Lautenschläger, F., Otto, O., et al. (2024) · European Journal of Immunology · doi:10.1002/eji.202350693 · Cited by 36 · see citing works
HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions
Cook, S., Lenardo, M. J., & Freeman, A. F. (2022) · Journal of Clinical Immunology · doi:10.1007/s10875-022-01327-0 · Cited by 24 · see citing works
- Authors
- Ritter, A. T., Kapnick, S. M., Murugesan, S., Schwartzberg, P. L., Griffiths, G. M., & Lippincott-Schwartz, J.
- Affiliations
- National Institutes of Health (US)
- University of Cambridge (GB)
- National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD 20892;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-07-17
- Volume
- 114
- Issue
- 32
- Pages
- E6585-E6594
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5559056
- OpenAlex
- W2735096673
- Cited by
- 104
- References
- 0
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 11 · 2023: 9 · 2022: 9 · 2021: 14 · 2020: 17 · 2019: 11 · 2018: 13 · 2017: 2
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome (103930, 100140)
- HHS | National Institutes of Health (NA)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- cytotoxic T lymphocytes, immunological synapse, cortical actin cytoskeleton, actin dynamics, phosphatidylinositol 4,5-bisphosphate, cytotoxicity
- MeSH terms
- rab27 GTP-Binding Proteins, Actins, Animals, Mice, Transgenic, CD8-Positive T-Lymphocytes, Phosphatidylinositol 4,5-Diphosphate, Secretory Vesicles, Mice, Immunological Synapses
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