Stepwise Cytoskeletal Polarization as a Series of Checkpoints in Innate but Not Adaptive Cytolytic Killing

Cytolytic killing is a major effector mechanism in the elimination of virally infected and tumor cells. The innate cytolytic effectors, natural killer (NK) cells, and the adaptive effectors, cytotoxic T cells (CTL), despite differential immune recognition, both use the same lytic mechanism, cytolyti...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 100; no. 13; pp. 7767 - 7772
Main Authors Wülfing, Christoph, Purtic, Bozidar, Klem, Jennifer, Schatzle, John D.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 24.06.2003
National Acad Sciences
Subjects
Actins
Actins - metabolism
Animals
Antineoplastic Agents - pharmacology
Biological Sciences
Calcium
Cells
Cellular biology
Cytoskeleton - immunology
Cytoskeleton - metabolism
Depsipeptides
Experimental procedures
Fluorescence
Green Fluorescent Proteins
Immune system
Killer Cells, Natural - metabolism
Luminescent Proteins - metabolism
Mice
Mice, SCID
Microscopy
Microtubule organizing center
Models, Biological
Natural killer cells
Natural killer T cells
Nocodazole - pharmacology
Peptides, Cyclic - pharmacology
T lymphocytes
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
Time Factors
Tubulin - metabolism
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Summary:Cytolytic killing is a major effector mechanism in the elimination of virally infected and tumor cells. The innate cytolytic effectors, natural killer (NK) cells, and the adaptive effectors, cytotoxic T cells (CTL), despite differential immune recognition, both use the same lytic mechanism, cytolytic granule release. Using live cell video fluorescence microscopy in various primary cell models of NK cell and CTL killing, we show here that on tight target cell contact, a majority of the NK cells established cytoskeletal polarity required for effective lytic function slowly or incompletely. In contrast, CTLs established cytoskeletal polarity rapidly. In addition, NK cell killing was uniquely sensitive to minor interference with cytoskeletal dynamics. We propose that the stepwise NK cell cytoskeletal polarization constitutes a series of checkpoints in NK cell killing. In addition, the use of more deliberate progression to effector function to compensate for inferior immune recognition specificity provides a mechanistic explanation for how the same effector function can be used in the different functional contexts of the innate and adaptive immune response.
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Edited by Jack L. Strominger, Harvard University, Cambridge, MA
This paper was submitted directly (Track II) to the PNAS office.
To whom correspondence should be addressed. E-mail: Christoph.Wuelfing@UTSouthwestern.edu.
C.W. and J.D.S. contributed equally to this work.
Abbreviations: NK, natural killer; CTL, cytotoxic T cell; LAK, lymphokine-activated killer; MTOC, microtubule organizing center; DIC, differential interference contrast.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1336920100