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

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. [Display omitted] •CD8+ T cell tolerance induces a transcriptionally and epigenetically distinct state•Tolerant cells diverge early and progressively from effector cells•Tolerant cells resemble stem-like cells from tumor-draining lymph nodes•Up-regulation of protein translation by antigen and inflammation overrides tolerance Steady-state antigen recognition triggers tolerant CD8+ T cell states that restrain autoimmunity and limit anti-cancer immunity. The relationship between tolerant states and other differentiation states remains unclear. Van Der Byl et al. demonstrate that tolerance triggers a transcriptionally and epigenetically distinct differentiation trajectory. The synergistic actions of strong TCR signaling and inflammation are required to override the tolerance checkpoint.