Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing

Wülfing, Christoph; Purtic, Bozidar; Klem, Jennifer; Schatzle, John D.

doi:10.1073/pnas.1336920100

Cited by 106 publications

(151 citation statements)

References 36 publications

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“…As a corroborating approach to interfere with actin dynamics, we blocked F-actin depolymerization with a small concentration of Jasplakinolide (Materials and Methods) (39,40). A similar yet slightly more drastic interference with actin dynamics was found (supplementary material) (41).…”

Section: Intact Actin Dynamics Are Required For the Accumulation Of Tmentioning

confidence: 78%

Regulation of Sustained Actin Dynamics by the TCR and Costimulation as a Mechanism of Receptor Localization

Tskvitaria-Fuller

Rozelle²,

Yin³

et al. 2003

The Journal of Immunology

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112

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The localization of receptors, signaling intermediates, and cytoskeletal components at the T cell/APC interface is thought to be a major determinant of efficient T cell activation. However, important questions remain open. What are the dynamics of the T cell cytoskeleton as a potential mediator of such localization? How are they regulated by the TCR and costimulatory receptors? Do they actually mediate receptor localization? In this study, we have addressed these questions. Even under limiting T cell activation conditions, actin accumulated immediately and transiently at the T cell/APC interface, the microtubule organizing center reoriented toward it. In contrast, sustained (>5 min) actin accumulation in highly dynamic patterns depended on an optimal T cell stimulus: high concentrations of the strong TCR ligand agonist peptide/MHC and engagement of the costimulatory receptors CD28 and LFA-1 were required in an overlapping, yet distinct, fashion. Intact sustained actin dynamics were required for interface accumulation of TCR/MHC in a central pattern and for efficient T cell proliferation, as established using a novel approach to selectively block only the sustained actin dynamics. These data suggest that control of specific elements of actin dynamics by TCR and costimulatory receptors is a mechanism to regulate the efficiency of T cell activation.

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Section: Intact Actin Dynamics Are Required For the Accumulation Of Tmentioning

confidence: 78%

Regulation of Sustained Actin Dynamics by the TCR and Costimulation as a Mechanism of Receptor Localization

Tskvitaria-Fuller

Rozelle²,

Yin³

et al. 2003

The Journal of Immunology

Self Cite

112

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“…The number of stable conjugates between CD16 + lymphocytes and K562 cells was determined by using both flow cytometry and fluorescent microscopy. However, not all NK cell-target cell interactions result in target cell lysis (Frederick et al, 1996;Wulfing et al 2003). Further, it has been shown that there are regulatory check points beyond stable ligation of the NK cell to the target cell that determine NK cell lytic activity (Bryceson et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The formation of a synapse does not necessarily lead to the NK meditated lysis of the target cell, but it is required for NK cell mediated lysis of the target cell (Wulfing et al 2003). Thus, while stable adhesion is required for granule release and blockage of the adhesion will block target cell lysis, stable adhesion of the NK cell to the target does not necessitate the release of the granules and the lysis of the target cell (Vyas et al 2001;Vyas et al 2002).…”

Section: Nk Cells Are Innate Immune Effector Cells Which Eliminate VImentioning

confidence: 99%

In vitro atrazine-exposure inhibits human natural killer cell lytic granule release

Rowe

Brundage

Barnett

2007

Toxicology and Applied Pharmacology

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The herbicide atrazine is a known immunotoxicant and an inhibitor of human Natural Killer (NK) cell lytic function. The precise changes in NK cell lytic function following atrazine exposure have not been fully elucidated. The current study identifies the point at which atrazine exerts its affect on the stepwise process of human NK cell mediated lyses of the K562 target cell line. Using intracellular staining of human peripheral blood lymphocytes, it was determined that a 24 h in vitro exposure to atrazine did not decrease the level of NK cell lytic proteins granzyme A, granzyme B or perforin. Thus, it was hypothesized that atrazine exposure was inhibiting the ability of the NK cells to bind to the target cell and subsequently inhibit the release of lytic protein from the NK cell. To test this hypothesis, flow cytometry and fluorescent microscopy were employed to analyze NK cell-target cell co-cultures following atrazine exposure. These assays demonstrated no significant decrease in the level of target cell binding. However, the levels of NK intracellular lytic protein retained and the amount of lytic protein released were assessed following a 4 h incubation with K562 target cells. The relative level of intracellular lytic protein was 25-50% higher, and the amount of lytic protein released was 55-65% less in atrazine treated cells than vehicle treated cells following incubation with the target cells. These results indicate that ATR exposure inhibits the ability of NK cells to lyse target cells by blocking lytic granule release without affecting the ability of the NK cell to form stable conjugates with target cells.

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“…Several key steps before target cell lysis are necessary for NK cell eff ector function ( 1,2 ), and inhibition of any of these steps would decrease NK cell cytotoxicity. To elucidate where myosin II plays its critical role, NK cell eff ector function was analyzed at each step.…”

Section: Evaluation Of Nkis Formationmentioning

confidence: 99%

Myosin IIA is required for cytolytic granule exocytosis in human NK cells

Andzelm¹,

Chen²,

Krzewski³

et al. 2007

J Cell Biol

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Stepwise cytoskeletal polarization as a series of checkpoints in innate but not adaptive cytolytic killing

Cited by 106 publications

References 36 publications

Regulation of Sustained Actin Dynamics by the TCR and Costimulation as a Mechanism of Receptor Localization

Regulation of Sustained Actin Dynamics by the TCR and Costimulation as a Mechanism of Receptor Localization

In vitro atrazine-exposure inhibits human natural killer cell lytic granule release

Myosin IIA is required for cytolytic granule exocytosis in human NK cells

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