“…Even though T cell exhaustion is a progressive process that occurs over several weeks to months, the effector differentiation programs begin to diverge between acute and chronic infection within the first week of infection ( Wherry et al, 2007 ; Ahmadzadeh et al, 2009 ; Sen et al, 2016 ; Chen et al, 2019b , 2021 ; Yao et al, 2019 ; Zhang et al, 2019 ). More specifically, the effector cells in both acute and chronic LCMV infection are transcriptionally similar up to day 4.5 after infection ( Yao et al, 2019 ), but a significant transcriptional and epigenetic divergence begins a couple of days later and then continues for several more weeks ( Wherry et al, 2007 ; Ahmadzadeh et al, 2009 ; Sen et al, 2016 ; Philip et al, 2017 ; Chen et al, 2019b , 2021 ; Yao et al, 2019 ; Zhang et al, 2019 ). This time period coincides exactly with changes in the expression of the TF TOX, as it dwindles in antigen-specific CD8 + T cells in acute infection but becomes amplified in chronic infection and tumors ( Page et al, 2018 ; Yao et al, 2019 ; Khan et al, 2019 ).…”