FRI614 Rescuing Aging-associated CD4(+) T Cell Dysfunction Via Mitochondrial Transplantation

Disclosure: C.A. Headley: None. Mitochondrial dysfunction alters cellular metabolism, increases 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 and elderly humans, could abrogate aging-associated mitochondrial dysfunction and improve the functionality of aged CD4(+) T cells. Our results show that the delivery of exogenous mitochondria to aged T cells led to cellular and mitochondrial reprogramming. This was evidenced by significant mitochondrial proteome alterations that coincided with improved aerobic metabolism and decreased mitoROS in non-activated CD4(+) T cells from old mice that received healthy mitochondria. Compared to non-manipulated CD4(+) T cells, CD4(+) T cells that received functional mitochondria (i.e. mito-transferred CD4(+) T cells from old mice) showed improvements in activation-induced TCR-signaling kinetics that correlated with increased frequencies of CD4(+) T cells that displayed markers of activation (CD25), increased IL-2 production, as well as enhanced proliferation ex vivo. Immunodeficient mouse models (RAG-KO and TCR-KO) showed that the adoptive transfer of mito-transferred naive CD4(+) T cells, protected recipient mice from influenza A and M. tuberculosis infections and promoted effector memory T cell differentiation. Further, mito-transfer improved CD4(+) T cell activation in human T cells by decreasing activation-induced senescence. These findings support mitochondria as targets of therapeutic intervention in aging. Presentation: Friday, June 16, 2023