Stem-like precursors of exhausted Th cells upheld by a Tox-Myb-Eomes transcriptional hierarchy propagate Th cell responses in chronic infection.

CD4+ T helper (Th) cells are critical drivers of adaptive immunity, but how their responses are maintained during chronic infection remains unclear. Here, we identified a population of CD4+ T cells that expressed CD62L and the inhibitory receptor PD-1 and exhibited both features of exhaustion and stemness. These cells acted as precursors of T helper (pTh) cells and sustained Th cell immunity during chronic lymphocytic choriomeningitis virus (LCMV) infection, giving rise to type 1 (Th1) and follicular T helper (Tfh) cells and cytotoxic-like T cells. pTh cells developed under conditions of high antigen exposure and depended on exhaustion and stemness-associated transcription factors TOX, EOMES, and MYB. Consequently, the maintenance of mature Th cells was severely compromised when CD4+ T cells lacked these factors. pTh cells also contributed to Th1 cell expansion upon PD-1 blockade. Overall, our findings reveal a molecular program and cellular hierarchy that preserve long-term CD4+ Th cell responses during chronic infection and immunotherapy.