Extracellular Delivery of Functional Mitochondria Rescues the Dysfunction of CD4⁺ T Cells in Aging

Abstract

Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4+ T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4+ T cells that are isolated from old mice (aged CD4+ T cells), can abrogate aging‐associated mitochondrial dysfunction, and improve the aged CD4+ T cell functionality. The results show that the delivery of exogenous mitochondria to aged non‐activated CD4+ T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito‐transferred aged CD4+ T cells showed improvements in activation‐induced TCR‐signaling kinetics displaying markers of activation (CD25), increased IL‐2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG‐KO) showed that adoptive transfer of mito‐transferred naive aged CD4+ T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging.

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

“…Additionally, mito-transferred aged CD4 + T cells showed improvement in activation-induced TCR-signaling kinetics, markers of IL-2 signaling (CD25), increased IL-2 production, and enhanced proliferation ex vivo. Importantly, we showed that adoptive transfer of mito-transferred naive aged CD4 + T cells to RAG-KO mice protected them from M.tb infection [44]. These findings underscored the potential of targeted mitotransfer in rescuing aged lymphocytes, with important implications for future immunological and therapeutic studies for chronic infections and diseases [44].…”

“…Importantly, we showed that adoptive transfer of mito-transferred naive aged CD4 + T cells to RAG-KO mice protected them from M.tb infection [44]. These findings underscored the potential of targeted mitotransfer in rescuing aged lymphocytes, with important implications for future immunological and therapeutic studies for chronic infections and diseases [44].…”

“…In our previous study, we demonstrated that mito-transferred naïve CD4 + T cells from old mice had improved control of influenza A virus (IAV) or M.tb infection in RAG-KO mice [44]. Specific to the M.tb experiments, in comparison to M.tb infected-RAG-KO that received either naïve CD4 + T cells from old mice or no naive CD4 + T cells, the mice that received mito-transferred naïve CD4 + T cells from old mice had the lowest M.tb burden in the lung and spleen, at 21 days post-infection [44].…”

“…Mitochondrial dysfunction (mito-dysfunction) is a pivotal contributor to T cell exhaustion and senescence [24,29,35,[37][38][39][40][41][42][43] and can be characterized by reduced quality of mitochondrial DNA, decreased efficiency of the electron transport chain (ETC), irregular mitochondrial membrane potential (Δψm), and abnormal generation of reactive oxygen species (mitoROS) [24,29,35,[37][38][39][40][41][42][43]. Addressing mito-dysfunction could offer a therapeutic opportunity to enhance immune responses against TB [44]. This approach may also improve responses to anti-TB therapy, which usually involves a lengthy drug regimen, that becomes increasing hard to maintain in individuals such as the elderly due to their associated cytotoxicity [45].…”

“…Our previous studies indicated the potential of mitochondrial transplantation (mito-transfer) to improve the function of CD4 + T cells isolated from 18-22 month old (aged) mice conferring higher resistance against M.tb infection [44]. Mito-transfer is the process of delivering healthy/nondysfunctional mitochondria to diseased or dysfunctional cells, tissue, or organs to improve functionality [46][47][48][49][50][51].…”