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 like PD-1 blockade can re-invigorate T(EX) cells, but re-invigoration 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 compared to T(MEM) cells. Chromatin-accessibility profiling revealed 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.