Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells

Linda V. Sinclair; Tom Youdale; Laura Spinelli; Milica Gakovic; Alistair J. Langlands; Shalini Pathak; Andrew J.M. Howden; Ian G. Ganley; Doreen A. Cantrell

doi:10.1038/s41590-025-02090-1

Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells

Linda V. Sinclair (Lead / Corresponding author)
, Tom Youdale
, Laura Spinelli
, Milica Gakovic
, Alistair J. Langlands
, Shalini Pathak
, Andrew J.M. Howden
, Ian G. Ganley
, Doreen A. Cantrell (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

74 Downloads (Pure)

Abstract

Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive 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.

Original language	English
Pages (from-to)	429-443
Number of pages	32
Journal	Nature Immunology
Volume	26
DOIs	https://doi.org/10.1038/s41590-025-02090-1
Publication status	Published - 27 Feb 2025

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10.1038/s41590-025-02090-1Licence: CC BY

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Final published version, 9.59 MBLicence: CC BY

Cite this

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title = "Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells",

abstract = "Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive 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.",

author = "Sinclair, \{Linda V.\} and Tom Youdale and Laura Spinelli and Milica Gakovic and Langlands, \{Alistair J.\} and Shalini Pathak and Howden, \{Andrew J.M.\} and Ganley, \{Ian G.\} and Cantrell, \{Doreen A.\}",

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doi = "10.1038/s41590-025-02090-1",

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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.

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N2 - Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive 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.

AB - Autophagy shapes CD8 T cell fate; yet the timing, triggers and targets of this process are poorly defined. Herein, we show that naive CD8 T cells have high autophagic flux, and we identify an autophagy checkpoint whereby antigen receptor engagement and inflammatory cytokines acutely repress autophagy by regulating amino acid transporter expression and intracellular amino acid delivery. Activated T cells with high levels of amino acid transporters have low autophagic flux in amino-acid-replete conditions but rapidly reinduce autophagy when amino acids are restricted. A census of proteins degraded and fueled by autophagy shows how autophagy shapes CD8 T cell proteomes. In cytotoxic T cells, dominant autophagy substrates include cytolytic effector molecules, and amino acid and glucose transporters. In naive 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.

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JO - Nature Immunology

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Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells

Abstract

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Other files and links

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System Level Understanding of Protein Degradation Pathways in T Lymphocytes

Training the Next Generation of Scientists in Quantitative and Interdisciplinary Approaches to Biomedical Science (Doctoral Training Partnership)

Fluorescence Activated Cell Sorting for Cell Biology and Immunology (Equipment Grant)

Author Correction: Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells (Nature Immunology, (2025), 26, 3, (429-443), 10.1038/s41590-025-02090-1)

Cite this

Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells

Abstract

Access to Document

Other files and links

Fingerprint

Projects

System Level Understanding of Protein Degradation Pathways in T Lymphocytes

Training the Next Generation of Scientists in Quantitative and Interdisciplinary Approaches to Biomedical Science (Doctoral Training Partnership)

Fluorescence Activated Cell Sorting for Cell Biology and Immunology (Equipment Grant)

Research output

Author Correction: Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells (Nature Immunology, (2025), 26, 3, (429-443), 10.1038/s41590-025-02090-1)

Cite this