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

Headley, C. A.; Gautam, S.; Akhter, A.; Dwivedi, V.; Ault, R.; Torrelles, J. B.; Gelfond, J. A. L.; Turner, J.

doi:10.1101/2021.02.21.432151

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bioRxiv · 10.1101/2021.02.21.432151

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

Headley, C. A.·Gautam, S.·Akhter, A.·Dwivedi, V.·Ault, R.·Torrelles, J. B.·Gelfond, J. A. L.·Turner, J.

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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, we investigated whether the transfer of functional mitochondria into CD4+ T cells that were isolated from old mice (aged CD4+ T cells), could abrogate aging-associated mitochondrial dysfunction, and improve the aged CD4+ T cell functionality. Our 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.

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Headley, C. A., Gautam, S., Akhter, A., Dwivedi, V., Ault, R., Torrelles, J. B., Gelfond, J. A. L., Turner, J.. 2021-02-21. Extracellular Delivery of Functional Mitochondria Reverses the Dysfunction of CD4+ T Cells in Aging. https://doi.org/10.1101/2021.02.21.432151

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