PT  - JOURNAL ARTICLE
AU  - Sinclair, Linda V.
AU  - Youdale, Tom
AU  - Spinelli, Laura
AU  - Gakovic, Milica
AU  - Langlands, Alistair J.
AU  - Pathak, Shalini
AU  - Howden, Andrew J.M.
AU  - Ganley, Ian G.
AU  - Cantrell, Doreen A.
TI  - Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells
AID  - 10.1101/2024.06.10.598276
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.06.10.598276
4099  - http://biorxiv.org/content/early/2024/06/11/2024.06.10.598276.short
4100  - http://biorxiv.org/content/early/2024/06/11/2024.06.10.598276.full
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.