PRJNA546023
Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade.
We have recently defined a novel population of PD-1+ TCF1+ virus-specific CD8 T cells that function as resource cells during chronic LCMV infection and provide the proliferative burst seen after PD-1 blockade. Such CD8 T cells have been found in other chronic infections and also in cancer in mice and humans. These CD8 T cells exhibit stem-like properties undergoing self-renewal and also giving rise to the terminally differentiated (exhausted) CD8 T cells. Here we compared the epigenetic signature of stemlike CD8 T cells with exhausted CD8 T cells. ATAC-seq analysis showed that stem-like CD8 T cells had a unique signature implicating activity of TCF (HMG family) and NF-?B (RHD family) members. In addition, transcription factor networks including Tcf7, Id3, and Bach2 were enriched in stem-like CD8 T cells. In contrast, exhausted CD8 T cells enriched accessible sites for ETS and Runx motifs in addition to a network encompassing Prdm1 and Il10. We also compared the epigenetic signatures of the two CD8 T-cell subsets from chronically infected mice with effector and memory CD8 T cells generated after an acute LCMV infection. Both CD8 T-cell subsets generated during chronic infection were strikingly different from CD8 T-cell subsets from acute infection. Interestingly, the stem-like CD8 T-cell subset from chronic infection, despite sharing key functional properties with memory CD8 T cells, had a very distinct epigenetic program. These results show that the chronic stem-like CD8 T-cell program represents a specific adaptation of the T-cell response to persistent antigenic stimulation.