Mitochondrial Transplantation promotes protective effector and memory CD4+T cell response duringMycobacterium tuberculosisinfection and diminishes exhaustion and senescence in elderly CD4+T cells

Author:

Headley Colwyn A.ORCID,Gautam Shalini,Olmo-Fontanez AngelicaORCID,Garcia-Vilanova Andreu,Dwivedi Varun,Schami Alyssa,Weintraub Susan,Tsao Philip S.,Torrelles Jordi B.,Turner Joanne

Abstract

AbstractTuberculosis (TB), caused by the bacteriumMycobacterium 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 againstM.tb. Chronic infections, such asM.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 duringM.tbinfection 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.

Publisher

Cold Spring Harbor Laboratory

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