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

In this study, we examined the differentiation trajectory of CD8+ T cells undergoing peripheral tolerance by scRNAseq and ATACseq and compared their differentiation to that of CD8+ T cells under going effector/memory differentiation or exhaustion. We found that tolerant CD8+ T cells adopt a unique differentiation trajectory distinct from all other states examined. We additionally used bulk RNAseq to identify key gene modules controlled by antigen and/or bystander information. We found that tolerance was only breached by the combined actions of antigen load and inflammation, which synergistically induced gene modules linked to increased protein translation. Overall design: Cells were index sorted and scRNAseq was performed by MARS-seq. The open chromatin regions of Naïve, Tolerance and Effector CD8+ T cells was assessed and compared by ATACseq. Using bulk RNAseq, we examined the contribution of antigen load and bystander inflammation to the transcriptional profile of CD8+ T cells undergoing peripheral tolerance.