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Mitochondrial translation is required for sustained killing by cytotoxic T cells.

Accepted version
Peer-reviewed

Type

Article

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Abstract

T cell receptor activation of naïve CD8+ T lymphocytes initiates their maturation into effector cytotoxic T lymphocytes (CTLs), which can kill cancer and virally infected cells. Although CTLs show an increased reliance on glycolysis upon acquisition of effector function, we found an essential requirement for mitochondria in target cell–killing. Acute mitochondrial depletion in USP30 (ubiquitin carboxyl-terminal hydrolase 30)–deficient CTLs markedly diminished killing capacity, although motility, signaling, and secretion were all intact. Unexpectedly, the mitochondrial requirement was linked to mitochondrial translation, inhibition of which impaired CTL killing. Impaired mitochondrial translation triggered attenuated cytosolic translation, precluded replenishment of secreted killing effectors, and reduced the capacity of CTLs to carry out sustained killing. Thus, mitochondria emerge as a previously unappreciated homeostatic regulator of protein translation required for serial CTL killing.

Description

Keywords

Adenosine Triphosphate, Animals, Cell Movement, Cells, Cultured, Cytotoxicity, Immunologic, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Mitochondrial Proteins, Protein Biosynthesis, T-Lymphocytes, Cytotoxic, Thiolester Hydrolases

Journal Title

Science

Conference Name

Journal ISSN

0036-8075
1095-9203

Volume Title

374

Publisher

American Association for the Advancement of Science (AAAS)
Sponsorship
Wellcome Trust (103930/Z/14/Z)
Wellcome Trust (108415/Z/15/Z)
Wellcome Trust (217100/Z/19/Z)
Wellcome Trust (100156/Z/12/Z)
Medical Research Council (MC_UU_00015/7)
Wellcome Trust (204017/Z/16/Z)