Single-Cell RNA-Seq Reveals TOX as a Key Regulator of CD8(+) T cell Persistence in Chronic Infection

Progenitor-like CD8(+) T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including TCF1, but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing single-cell transcriptomes and epigenetic profiles of CD8(+) T cells responding to acute and chronic viral infections, we found that progenitor-like CD8(+) T cells became distinct from memory precursors before the peak of the T-cell response. We discovered a co-expression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursors. Moreover, TOX promoted persistence of antiviral CD8(+) T cells and was required for the programming of progenitor-like CD8(+) T cells. Thus, long-term CD8(+) T-cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.