TOX sustains the longevity and multipotency of CD4 Tprog cells during chronic LCMV infection

Progenitor CD4 T cells (Tprog) develop during chronic viral infection and cancer and retain developmental plasticity to replenish Tfh and Th1 populations over time. Although considerable attention has been given to progenitor CD8 T cells, the distinct biological roles and multiple fates of CD4 T cells raise questions about the molecular circuitry controlling CD4 Tprog in settings of chronic stimulation. Here, we interrogated the impact of the HMG-box transcription factor (TF) TOX on the developmental flexibility of virus-specific CD4 T cells and the role of this TF in coordinating the transcriptional and epigenetic program of CD4 Tprog during chronic infection. These studies revealed key elements of CD4 Tprog biology that are central to sustaining T cell responses to persistent infection. First, TOX was dispensable for CD4 Tprog development but required for maintenance and function of these cells over time. Second, TOX promoted CD4 Tprog maintenance and survival by regulating expression of BIM and BCL-2. Third, loss of TOX in CD4 Tprog resulted in transcriptional and epigenetic dysregulation, highlighted by loss of TCF-1 pathway activity and gain of NFAT, NFkB, and RUNX-coordinated transcriptional circuitry. Finally, functional interrogation revealed a key role for TOX in the multipotent potential of CD4 Tprog to differentiate into Th1-like or Tfh-like cells during chronic viral infection. These data reveal a TOX-driven molecular network that sustains the core function of CD4 Tprog, highlighting a role for this TF not just in terminal exhaustion, but also in stem-like CD4 T cells that support development of downstream CD4 T cell subsets during persisting antigen stimulation.