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 T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. 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 Tox 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.
Yao, C; Sun, H-W; Lacey, NE; Ji, Y; Moseman, EA; Shih, H-Y; Heuston, EF; Kirby, M; Anderson, S; Cheng, J; Khan, O; Handon, R; Reilley, J; Fioravanti, J; Hu, J; Gossa, S; Wherry, EJ; Gattinoni, L; McGavern, DB; O'Shea, JJ; Schwartzberg, PL; Wu, T
Volume / Issue
Start / End Page
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)