RT Journal Article
SR Electronic
T1 Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.06.10.598276
DO 10.1101/2024.06.10.598276
A1 Sinclair, Linda V.
A1 Youdale, Tom
A1 Spinelli, Laura
A1 Gakovic, Milica
A1 Langlands, Alistair J.
A1 Pathak, Shalini
A1 Howden, Andrew J.M.
A1 Ganley, Ian G.
A1 Cantrell, Doreen A.
YR 2024
UL http://biorxiv.org/content/early/2024/06/11/2024.06.10.598276.abstract
AB Autophagy is important for CD8 T-cells but autophagy timing, triggers and targets are poorly defined. Herein, we show naïve CD8-T cells have high autophagic flux and identify an autophagy checkpoint whereby antigen receptor engagement represses autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Effector cytotoxic T cells with high levels of amino acid transporters driven by proinflammatory cytokines have low autophagic flux but rapidly reinduce autophagy when amino acid restricted. A census of proteins degraded and fuelled by autophagy shows how autophagy shapes CD8-T cell proteomes. In cytotoxic T-cells, dominant autophagy substrates include cytolytic effector molecules, amino acid and glucose transporters. In naïve T-cells mitophagy dominates and selective mitochondrial pruning supports the expression of molecules that coordinate T-cell migration and survival. Autophagy thus differentially prunes naive and effector T-cell proteomes and is dynamically repressed by antigen receptors and inflammatory cytokines to shape T-cell differentiation.Competing Interest StatementThe authors have declared no competing interest.