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. 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.