Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation

Exhausted CD8 T cells (T-EX) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate T-EX cells, but reinvigoration is not durable. A major unanswered question is whether T-EX cells differentiate into functional durable memory T cells (T-MEM) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, T-EX cells partially (re)acquire phenotypic and transcriptional features of T-MEM cells. These 'recovering' T-EX cells originated from the T cell factor (TCF-1(+)) T-EX progenitor subset. Nevertheless, the recall capacity of these recovering T-EX cells remained compromised as compared to T-MEM cells. Chromatin-accessibility profiling revealed a failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for T-EX cell-targeted immunotherapies. Wherry and colleagues examine whether exhausted T cells (T-EX) can differentiate into functional memory T cells (T-MEM) when chronic antigen is withdrawn. Using the chronic LCMV infection mouse model, they show that 'recovering' T-EX cells (REC-T-EX) only partially recover immunophenotypic and functional characteristics of T-MEM cells. The epigenomic status of REC-T-EX cells more closely resembles that of T-EX cells, and, upon rechallenge, the REC-T-EX cells were still compromised in their ability to respond to virus.