CD4+ T cells are essential for immune responses, but the molecular mechanisms governing their function remain unclear. This study identifies a stem-like program that regulates CD4+ T cell responses in transplantation. Single-cell transcriptomic analysis reveals that naive CD4+ T cells develop into TCF1hi effector precursor (TEP) cells and TCF1- CXCR6+ effectors in transplant recipients. TCF1hi TEP cells have self-renewal and effector differentiation potential, while TCF1- CXCR6+ effectors lose proliferation capacity and fail to reject allografts. TCF1 sustains TEP cells, while IRF4 and LDHA regulate effector differentiation. Deletion of IRF4 or LDHA in T cells leads to transplant acceptance. These findings reveal a stem-like program controlling CD4+ TEP cell function and have implications for immunotherapy. CD4+ T cells differentiate into various effector subsets, but the mechanisms maintaining their function are not fully understood. Stem-like TCF1+ CD4+ TEP cells, identified in multiple sclerosis and chronic infection models, exhibit self-renewal and differentiation potential. TCF1 is crucial for T cell biology, including thymic development and memory T cell generation. IRF4 is necessary for differentiation of T helper cells. TCF1hi TEP cells sustain themselves, while IRF4 and LDHA govern effector differentiation. Aerobic glycolysis is critical for effector function, with LDHA playing a key role. TCF1hi TEP cells continuously replenish effector cells to drive transplant rejection. IRF4 and TCF1 regulate distinct stem-like features of CD4+ TEP cells. scRNA-seq identifies LDHA as a regulator of CD4+ T cell alloimmunity. LDHA is essential for effector differentiation, and its deletion leads to transplant acceptance. These findings highlight the importance of stem-like CD4+ TEP cells in immune responses and suggest new strategies for immunotherapy.CD4+ T cells are essential for immune responses, but the molecular mechanisms governing their function remain unclear. This study identifies a stem-like program that regulates CD4+ T cell responses in transplantation. Single-cell transcriptomic analysis reveals that naive CD4+ T cells develop into TCF1hi effector precursor (TEP) cells and TCF1- CXCR6+ effectors in transplant recipients. TCF1hi TEP cells have self-renewal and effector differentiation potential, while TCF1- CXCR6+ effectors lose proliferation capacity and fail to reject allografts. TCF1 sustains TEP cells, while IRF4 and LDHA regulate effector differentiation. Deletion of IRF4 or LDHA in T cells leads to transplant acceptance. These findings reveal a stem-like program controlling CD4+ TEP cell function and have implications for immunotherapy. CD4+ T cells differentiate into various effector subsets, but the mechanisms maintaining their function are not fully understood. Stem-like TCF1+ CD4+ TEP cells, identified in multiple sclerosis and chronic infection models, exhibit self-renewal and differentiation potential. TCF1 is crucial for T cell biology, including thymic development and memory T cell generation. IRF4 is necessary for differentiation of T helper cells. TCF1hi TEP cells sustain themselves, while IRF4 and LDHA govern effector differentiation. Aerobic glycolysis is critical for effector function, with LDHA playing a key role. TCF1hi TEP cells continuously replenish effector cells to drive transplant rejection. IRF4 and TCF1 regulate distinct stem-like features of CD4+ TEP cells. scRNA-seq identifies LDHA as a regulator of CD4+ T cell alloimmunity. LDHA is essential for effector differentiation, and its deletion leads to transplant acceptance. These findings highlight the importance of stem-like CD4+ TEP cells in immune responses and suggest new strategies for immunotherapy.