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 effector precursor (T) cells and TCF1CXCR6 effectors in transplant recipients. The TCF1CXCR6CD4 effectors lose proliferation capacity and do not reject allografts upon adoptive transfer into secondary hosts. By contrast, the TCF1CD4 T cells have dual features of self-renewal and effector differentiation potential, and allograft rejection depends on continuous replenishment of TCF1CXCR6 effectors from TCF1CD4 T cells. Mechanistically, TCF1 sustains the CD4 T cell population, whereas the transcription factor IRF4 and the glycolytic enzyme LDHA govern the effector differentiation potential of CD4 T 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 cells and have implications for T cell-related immunotherapies.