Open AccessEpigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation
Author(s) -
Mohamed S. Abdel-Hakeem,
Sasikanth Manne,
Jean-Christophe Beltra,
Erietta Stelekati,
Zeyu Chen,
Kito Nzingha,
Mohammed-Alkhatim Ali,
John L. Johnson,
Josephine R. Giles,
Divij Mathew,
Allison R. Greenplate,
Golnaz Vahedi,
E. John Wherry
Publication year - 2021
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-021-00975-5
Subject(s) - epigenetics , cytotoxic t cell , biology , chromatin , immunology , antigen , immunotherapy , immune system , microbiology and biotechnology , cancer research , genetics , in vitro , gene
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.