Single-Cell Transcriptomics Identifies TOX as a Key Transcriptional Regulator of Progenitor-Like CD8 T Cells in Chronic Infection [ChIP-seq]

Stem-like CD8 T cells maintain long-term antiviral CD8 immunity during chronic infection, and share regulatory pathways with memory precursor effector cells generated after acute infection. However, it is unclear whether stem-like CD8 T cells require distinct transcriptional and epigenetic regulation for their longevity and adaptation to the immunosuppressive environment in chronic infection. Here, our comparison of single-cell transcriptomes and epigenetic profiles of CD8 T cells responding to acute and chronic viral infections revealed that stem-like CD8 T cells became distinct from memory precursors before clonal expansion ended. We found that a coexpression gene module containing Tox exhibited higher transcriptional activities and active histone marks in stem-like T cells than memory precursors. Moreover, TOX promoted persistence of antiviral CD8 T cells, and was required for stem-like CD8 differentiation. Our results indicate that stem-like CD8 T cells require unique transcriptional and epigenetic programs for their differentiation and persistence during chronic viral infection. Overall design: Single-cell tcranscriptomic and epigentic analysis of antigen specific CD8 T cells after acute and chronic viral infeciton. Transcrptome analysis of TOX over expression in antigen specific CD8 T cells after chornic viral infection.