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

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.