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^hiCD4⁺ 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^hiCD4⁺ 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.