Mohamed Abdel-Hakeem

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

Exhausted CD8 T cells (TEX) are a distinct lineage of T cells associated with failure to cure chronic viral infections and cancer. Although immunotherapies such as PD-1 blockade can re-invigorate TEX, this re-invigoration is not durable. A major unanswered question is whether TEX can differentiate into durable and functional memory CD8 T cells (TMEM) if antigen is cleared. Here, we found that upon eliminating chronic antigenic stimulation, TEX partially (re)acquire phenotypic and transcriptional features of TMEM. These “recovering” TEX originated from the TCF-1+ TEX progenitor subset. Nevertheless, the recall capacity of these recovering-TEX remained highly compromised compared to TMEM. Chromatin-accessibility profiling revealed a failure to recover core TMEM epigenetic circuits and maintenance of a largely TEX open chromatin landscape. Despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. Thus, epigenetic remodeling represents an important consideration for future TEX targeted immunotherapies.