Using a mouse model of peripheral tolerance, Van Der Byl, Nussing, and Peters et al. showed that soon after in vivo exposure to self-antigen, self-reactive CD8+ T cells expressed phenotypic, transcriptomic, and epigenetic profiles that minimally overlapped with CD8+ naïve T, TEFF and TEX cells, and resembled aberrantly primed CD8+ T cells from tumor-reactive TDLNs. Self-reactive CD8+ T cells prematurely exited the cell cycle, and their differentiation toward tolerance diverged early from that of CD8+ TEFF cells. Breaking CD8+ T cell tolerance required synergistic robust TCR and inflammatory signals that induced MYC-dependent protein translation.
Contributed by Paula Hochman
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.
Author Info: (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 Immunolo
Author Info: (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) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (5) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (7) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (8) Department of Pathology, University of Chicago, Chicago, IL, USA. (9) Garvan Institute of Medical Research, Sydney, NSW, Australia; John Curtin School of Medical Research, ANU, Canberra, ACT, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (13) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. (15) Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. (16) 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. (17) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (18) Faculty of Physics and Center for Nanoscience, Ludwig Maximilian University, Munich, Germany; Max Planck Institute of Biochemistry, Martinsried, Germany. (19) Institute of Materials, School of Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Interfaculty Bioengineering Institute, School of Engineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. (20) The Frazer Institute, The University of Queensland, Brisbane, QLD, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. (21) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (22) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia. (23) 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. (24) Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. (25) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (26) School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia. (27) The Kirby Institute for Infection and Immunity, UNSW, Sydney, NSW, Australia; School of Medical Sciences, Faculty of Medicine, UNSW, Sydney, NSW, Australia. Electronic address: luciani@unsw.edu.au. (28) 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: ian.parish@petermac.org.
