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Single-cell RNA-seq Reveals TOX as a Key Regulator of CD8 + T Cell Persistence in Chronic Infection (P14_2 batches)
Chen Yao, Hong-Wei Sun, Neal E. Lacey, Yun Ji, E. Ashley Moseman, Han-Yu Shih, Elisabeth F. Heuston, Martha Kirby, Stacie Anderson, Jun Cheng, Omar Khan, Robin Handon, Julie Reilley, Jessica Fioravanti, Jinhui Hu2, Selamawit Gossa, E. John Wherry, Luca Gattinoni, Dorian B. McGavern, John J. O<e2><80><99>Shea, Pamela L. Schwartzberg and Tuoqi Wu
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 T cell-specific tran-scription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environ-ment. By comparing the 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 precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing To x that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the 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.