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Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4310-4319. doi: 10.1073/pnas.1913220117. Epub 2020 Feb 10.

Centrioles control the capacity, but not the specificity, of cytotoxic T cell killing.

Author information

1
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
2
Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College, New York, NY 10065.
3
Department of Biomedical Engineering, Columbia University, New York, NY 10027.
4
Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
5
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
6
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065; husem@mskcc.org.

Abstract

Immunological synapse formation between cytotoxic T lymphocytes (CTLs) and the target cells they aim to destroy is accompanied by reorientation of the CTL centrosome to a position beneath the synaptic membrane. Centrosome polarization is thought to enhance the potency and specificity of killing by driving lytic granule fusion at the synapse and thereby the release of perforin and granzymes toward the target cell. To test this model, we employed a genetic strategy to delete centrioles, the core structural components of the centrosome. Centriole deletion altered microtubule architecture as expected but surprisingly had no effect on lytic granule polarization and directional secretion. Nevertheless, CTLs lacking centrioles did display substantially reduced killing potential, which was associated with defects in both lytic granule biogenesis and synaptic actin remodeling. These results reveal an unexpected role for the intact centrosome in controlling the capacity but not the specificity of cytotoxic killing.

KEYWORDS:

T cell; centriole; centrosome; cytotoxicity; microtubule

PMID:
32041868
PMCID:
PMC7049148
[Available on 2020-08-10]
DOI:
10.1073/pnas.1913220117

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