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.