TY - JOUR
T1 - Mitochondrial translation is required for sustained killing by cytotoxic T cells
AU - Lisci, Miriam
AU - Barton, Philippa R.
AU - Randzavola, Lyra O.
AU - Ma, Claire Y.
AU - Marchingo, Julia M.
AU - Cantrell, Doreen A.
AU - Paupe, Vincent
AU - Prudent, Julien
AU - Stinchcombe, Jane C.
AU - Griffiths, Gillian M.
N1 - Funding
Wellcome: 103930
Wellcome: 108415
Wellcome: 217100
Wellcome: 220543
Wellcome: 100156
Wellcome: 205023
Medical Research Council: MC_UU_0015/7
Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/10/15
Y1 - 2021/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85117295348&partnerID=8YFLogxK
U2 - 10.1126/science.abe9977
DO - 10.1126/science.abe9977
M3 - Article
C2 - 34648346
AN - SCOPUS:85117295348
VL - 374
JO - Science
JF - Science
SN - 0036-8075
IS - 6565
ER -