The CD8+ T cell tolerance checkpoint triggers a distinct differentiation state defined by protein translation defects

Willem Van Der Byl; Simone Nüssing; Timothy J Peters; Antonio Ahn; Hanjie Li; Guy Ledergor; Eyal David; Andrew S Koh; Mayura V Wagle; Christian Deo T Deguit; Maria N de Menezes; Avraham Travers; Shienny Sampurno; Kelly M Ramsbottom; Rui Li; Axel Kallies; Paul A Beavis; Ralf Jungmann; Maartje M C Bastings; Gabrielle T Belz; Shom Goel; Joseph A Trapani; Gerald R Crabtree; Howard Y Chang; Ido Amit; Chris C Goodnow; Fabio Luciani; Ian A Parish

doi:10.1016/j.immuni.2024.04.026

The CD8⁺ T cell tolerance checkpoint triggers a distinct differentiation state defined by protein translation defects

Immunity. 2024 Jun 11;57(6):1324-1344.e8. doi: 10.1016/j.immuni.2024.04.026. Epub 2024 May 21.

Authors

Willem Van Der Byl¹, Simone Nüssing², Timothy J Peters³, Antonio Ahn², Hanjie Li⁴, Guy Ledergor⁴, Eyal David⁴, Andrew S Koh⁵, Mayura V Wagle⁶, Christian Deo T Deguit⁷, Maria N de Menezes², Avraham Travers⁷, Shienny Sampurno⁷, Kelly M Ramsbottom⁷, Rui Li⁸, Axel Kallies⁹, Paul A Beavis², Ralf Jungmann¹⁰, Maartje M C Bastings¹¹, Gabrielle T Belz¹², Shom Goel², Joseph A Trapani², Gerald R Crabtree¹³, Howard Y Chang⁸, Ido Amit⁴, Chris C Goodnow¹⁴, Fabio Luciani¹⁵, Ian A Parish¹⁶

Affiliations

¹ The Kirby Institute for Infection and Immunity, UNSW, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW, Australia.
² Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
³ Garvan Institute of Medical Research, Sydney, NSW, Australia; University of New South Wales Sydney, Sydney, NSW, Australia.
⁴ Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
⁵ Department of Pathology, University of Chicago, Chicago, IL, USA.
⁶ Garvan Institute of Medical Research, Sydney, NSW, Australia; John Curtin School of Medical Research, ANU, Canberra, ACT, Australia.
⁷ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁸ Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
⁹ The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia.
¹⁰ Faculty of Physics and Center for Nanoscience, Ludwig Maximilian University, Munich, Germany; Max Planck Institute of Biochemistry, Martinsried, Germany.
¹¹ Institute of Materials, School of Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Interfaculty Bioengineering Institute, School of Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
¹² The Frazer Institute, The University of Queensland, Brisbane, QLD, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
¹³ Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA; Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁵ The Kirby Institute for Infection and Immunity, UNSW, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW, Australia. Electronic address: [email protected].
¹⁶ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia; John Curtin School of Medical Research, ANU, Canberra, ACT, Australia. Electronic address: [email protected].

PMID: 38776918
DOI: 10.1016/j.immuni.2024.04.026

Abstract

Peripheral CD8⁺ T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8⁺ T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors. Tolerant cells diverged early and progressively from effector cells, adopting a transcriptionally and epigenetically distinct state within 60 h of antigen encounter. Breaching tolerance required the synergistic actions of strong T cell receptor (TCR) signaling and inflammation, which cooperatively induced gene modules that enhanced protein translation. Weak TCR signaling during bystander infection failed to breach tolerance due to the uncoupling of effector gene expression from protein translation. Thus, tolerance engages a distinct differentiation trajectory enforced by protein translation defects.

Keywords: CD8(+) T cell; autoimmunity; cancer; differentiation; dysfunction; effector T cell; exhaustion; immunotherapy; stem-like T cell; tolerance.

MeSH terms

Animals
Autoantigens / immunology
CD8-Positive T-Lymphocytes* / immunology
Cell Differentiation* / immunology
Immune Tolerance* / immunology
Mice
Mice, Inbred C57BL
Protein Biosynthesis* / immunology
Receptors, Antigen, T-Cell* / immunology
Receptors, Antigen, T-Cell* / metabolism
Signal Transduction / immunology

Substances

Receptors, Antigen, T-Cell
Autoantigens

Abstract

MeSH terms

Substances

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