Mitochondrial Transplantation Promotes Protective Effector and Memory CD4+ T Cell Response During Mycobacterium Tuberculosis Infection and Diminishes Exhaustion and Senescence in Elderly CD4+ T cells

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis ( M.tb ), is a major global health concern, particularly affecting those with weakened immune systems, including the elderly. CD4 + T cell response is crucial for immunity against M.tb , but chronic infections and aging can lead to T cell exhaustion and senescence, worsening TB disease. Mitochondrial dysfunction, prevalent in aging and chronic diseases, disrupts cellular metabolism, increases oxidative stress, and impairs T‐cell functions. This study investigates the effect of mitochondrial transplantation (mito‐transfer) on CD4 + T cell differentiation and function in aged mouse models and human CD4 + T cells from elderly individuals. Mito‐transfer in naïve CD4 + T cells is found to promote protective effector and memory T cell generation during M.tb infection in mice. Additionally, it improves elderly human T cell function by increasing mitochondrial mass and altering cytokine production, thereby reducing markers of exhaustion and senescence. These findings suggest mito‐transfer as a novel approach to enhance aged CD4 + T cell functionality, potentially benefiting immune responses in the elderly and chronic TB patients. This has broader implications for diseases where mitochondrial dysfunction contributes to T‐cell exhaustion and senescence.