CD4+ T cell immunity is dependent on an intrinsic stem-like program

CD4(+) T cells are central to various immune responses, but the molecular programs that drive and maintain CD4(+) T cell immunity are not entirely clear. Here we identify a stem-like program that governs the CD4(+) T cell response in transplantation models. Single-cell-transcriptomic analysis revealed that naive alloantigen-specific CD4(+) T cells develop into TCF1(hi) effector precursor (T-EP) cells and TCF1(-)CXCR6(+) effectors in transplant recipients. The TCF1(-)CXCR6(+)CD4(+) effectors lose proliferation capacity and do not reject allografts upon adoptive transfer into secondary hosts. By contrast, the TCF1(hi)CD4(+) T-EP cells have dual features of self-renewal and effector differentiation potential, and allograft rejection depends on continuous replenishment of TCF1(-)CXCR6(+) effectors from TCF1(hi)CD4(+) T-EP cells. Mechanistically, TCF1 sustains the CD4(+) T-EP cell population, whereas the transcription factor IRF4 and the glycolytic enzyme LDHA govern the effector differentiation potential of CD4(+) T-EP cells. Deletion of IRF4 or LDHA in T cells induces transplant acceptance. These findings unravel a stem-like program that controls the self-renewal capacity and effector differentiation potential of CD4(+) T-EP cells and have implications for T cell-related immunotherapies.