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

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis ( M.tb ), remains a significant health concern worldwide, especially in populations with weakened or compromised immune systems, such as the elderly. Proper adaptive immune function, particularly a CD4 + T cell response, is central to host immunity against M.tb . Chronic infections, such as M.tb , as well as aging promote T cell exhaustion and senescence, which can impair immune control and promote progression to TB disease. Mitochondrial dysfunction contributes to T cell dysfunction, both in aging and chronic infections and diseases. Mitochondrial perturbations can disrupt cellular metabolism, enhance oxidative stress, and impair T-cell signaling and effector functions. This study examined the impact of mitochondrial transplantation (mito-transfer) on CD4 + T cell differentiation and function using aged mouse models and human CD4 + T cells from elderly individuals. Our study revealed that mito-transfer in naïve CD4 + T cells promoted the generation of protective effector and memory CD4 + T cells during M.tb infection in mice. Further, mito-transfer enhanced the function of elderly human T cells by increasing their mitochondrial mass and modulating cytokine production, which in turn reduced exhaustion and senescence cell markers. Our results suggest that mito-transfer could be a novel strategy to reestablish aged CD4 + T cell function, potentially improving immune responses in the elderly and chronic TB patients, with a broader implication for other diseases where mitochondrial dysfunction is linked to T cell exhaustion and senescence.