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. BelzShom Goel, Joseph A. Trapani, Gerald R. Crabtree, Howard Y. Chang, Ido Amit, Chris C. Goodnow, Fabio Luciani, Ian A. Parish

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1324-1344.e8
Number of pages30
JournalImmunity
Volume57
Issue number6
DOIs
StatePublished - 11 Jun 2024

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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