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

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 Jun 13

PMID 12802007

Citations 58

Authors

Christoph Wulfing

Bozidar Purtic

Jennifer Klem

John D Schatzle

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Spatial localization of CD16a at the human NK cell ADCC lytic synapse.

Ross P, Fatima H, Leaman D, Matthias J, Spencer K, Zwick M bioRxiv. 2024; .

PMID: 39149244 PMC: 11326286. DOI: 10.1101/2024.08.09.605851.

Human natural killer cells: Form, function, and development.

Mace E J Allergy Clin Immunol. 2022; 151(2):371-385.

PMID: 36195172 PMC: 9905317. DOI: 10.1016/j.jaci.2022.09.022.

Filamin A Is Required for NK Cell Cytotoxicity at the Expense of Cytokine Production Synaptic Filamentous Actin Modulation.

Kim N, Yi E, Kwon S, Park H, Kwon H, Kim H Front Immunol. 2022; 12:792334.

PMID: 35058930 PMC: 8764188. DOI: 10.3389/fimmu.2021.792334.

Horses for Courses in the Era of CARs: Advancing CAR T and CAR NK Cell Therapies.

Kulemzin S, Evsyukov I, Belovezhets T, Taranin A, Gorchakov A J Pers Med. 2021; 11(11).

PMID: 34834534 PMC: 8621371. DOI: 10.3390/jpm11111182.

NK Cells in a With Cancer: The Roles of Transcription Factors and Cytoskeleton.

Lee E, Wong D, Ding J Front Immunol. 2021; 12:734551.

PMID: 34594338 PMC: 8476995. DOI: 10.3389/fimmu.2021.734551.

References

Sancho D, Nieto M, Llano M, Rodriguez-Fernandez J, Tejedor R, Avraham S . The tyrosine kinase PYK-2/RAFTK regulates natural killer (NK) cell cytotoxic response, and is translocated and activated upon specific target cell recognition and killing. J Cell Biol. 2000; 149(6):1249-62. PMC: 2175114. DOI: 10.1083/jcb.149.6.1249. View

Eriksson M, LEITZ G, Fallman E, Axner O, Ryan J, Nakamura M . Inhibitory receptors alter natural killer cell interactions with target cells yet allow simultaneous killing of susceptible targets. J Exp Med. 1999; 190(7):1005-12. PMC: 2195645. DOI: 10.1084/jem.190.7.1005. View

Austin Taylor M, Bennett M, Kumar V, Schatzle J . Functional defects of NK cells treated with chloroquine mimic the lytic defects observed in perforin-deficient mice. J Immunol. 2000; 165(9):5048-53. DOI: 10.4049/jimmunol.165.9.5048. View

Germain R . The art of the probable: system control in the adaptive immune system. Science. 2001; 293(5528):240-5. DOI: 10.1126/science.1062946. View

Wulfing C, Sumen C, Sjaastad M, Wu L, Dustin M, Davis M . Costimulation and endogenous MHC ligands contribute to T cell recognition. Nat Immunol. 2001; 3(1):42-7. DOI: 10.1038/ni741. View

Kuhn J, Poenie M . Dynamic polarization of the microtubule cytoskeleton during CTL-mediated killing. Immunity. 2002; 16(1):111-21. DOI: 10.1016/s1074-7613(02)00262-5. View

Janeway Jr C, Medzhitov R . Innate immune recognition. Annu Rev Immunol. 2002; 20:197-216. DOI: 10.1146/annurev.immunol.20.083001.084359. View

Vyas Y, Maniar H, Dupont B . Cutting edge: differential segregation of the SRC homology 2-containing protein tyrosine phosphatase-1 within the early NK cell immune synapse distinguishes noncytolytic from cytolytic interactions. J Immunol. 2002; 168(7):3150-4. DOI: 10.4049/jimmunol.168.7.3150. View

Arase H, Mocarski E, Campbell A, Hill A, Lanier L . Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science. 2002; 296(5571):1323-6. DOI: 10.1126/science.1070884. View

10.

Orange J, Ramesh N, Remold-ODonnell E, Sasahara Y, Koopman L, Byrne M . Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci U S A. 2002; 99(17):11351-6. PMC: 123260. DOI: 10.1073/pnas.162376099. View

11.

Sanderson C . The mechanism of lymphocyte-mediated cytotoxicity. Biol Rev Camb Philos Soc. 1981; 56(2):153-97. DOI: 10.1111/j.1469-185x.1981.tb00346.x. View

12.

Carpen O, Virtanen I, Lehto V, Saksela E . Polarization of NK cell cytoskeleton upon conjugation with sensitive target cells. J Immunol. 1983; 131(6):2695-8. View

13.

Kupfer A, Dennert G, Singer S . Polarization of the Golgi apparatus and the microtubule-organizing center within cloned natural killer cells bound to their targets. Proc Natl Acad Sci U S A. 1983; 80(23):7224-8. PMC: 390027. DOI: 10.1073/pnas.80.23.7224. View

14.

Poenie M, Tsien R . Sequential activation and lethal hit measured by [Ca2+]i in individual cytolytic T cells and targets. EMBO J. 1987; 6(8):2223-32. PMC: 553622. DOI: 10.1002/j.1460-2075.1987.tb02494.x. View

15.

Kupfer A, Singer S . Cell biology of cytotoxic and helper T cell functions: immunofluorescence microscopic studies of single cells and cell couples. Annu Rev Immunol. 1989; 7:309-37. DOI: 10.1146/annurev.iy.07.040189.001521. View

16.

Trinchieri G . Biology of natural killer cells. Adv Immunol. 1989; 47:187-376. PMC: 7131425. DOI: 10.1016/s0065-2776(08)60664-1. View

17.

Pircher H, Burki K, Lang R, Hengartner H, Zinkernagel R . Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature. 1989; 342(6249):559-61. DOI: 10.1038/342559a0. View

18.

Garni-Wagner B, Purohit A, Mathew P, Bennett M, Kumar V . A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells. J Immunol. 1993; 151(1):60-70. View

19.

Cramer L . Role of actin-filament disassembly in lamellipodium protrusion in motile cells revealed using the drug jasplakinolide. Curr Biol. 1999; 9(19):1095-105. DOI: 10.1016/s0960-9822(99)80478-3. View

20.

Lauwerys B, Renauld J, Houssiau F . Synergistic proliferation and activation of natural killer cells by interleukin 12 and interleukin 18. Cytokine. 1999; 11(11):822-30. DOI: 10.1006/cyto.1999.0501. View