TCF1 is required for the generation of TCF1highTim3low virus-specific CD8 T cells

T-cell exhaustion is frequently observed during chronic viral infection and cancer. How exhausted T cells persist in the presence of immunosuppression is unclear. Here, we showed that virus-specific CD8 T cells differentiate into Tfh-like TCF1highTim3lowBlimp1low progenitors before the chronic phase of viral infection, which persist better than and can give rise to more terminal TCF1lowTim3highBlimp1high cells. Differentiation of TCF1high cells is driven by master regulator TCF1. Cell-intrinsic TCF1 deficiency led to sharp contraction and eventual deletion of virus-specific CD4 and CD8 T cells and uncontrolled viremia 1) tetramer+ WT or Tcf7 cKO CD8 T cells were sorted from day 7 LCMV clone 13 infected mice; 2) tetramer+ Blimp1lowTim3low or Blimp1highTim3high CD8 T cells were sorted from day 7 LCMV clone 13 infected mice; 3) empty MSCV-IRES-GFP control construct or TCF1 over-expression construct transduced P14 cells were sorted from mice on day 8 p.i.. RNA was purified from sorted samples.