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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This version of the manuscript includes more in vitro data and in vivo proof of principle that mito-transfer improves the functionality of aged CD4+ T cells. Mito-transferred CD4+ T cells from old mice displayed enhanced intracellular phosphorylation of key proteins essential to TCR signal transduction, increased cellular production of cytokines including IL-2, increased the number of cells expressing CD25, and improved cellular proliferation after ex vivo activation. Importantly, the adoptive transfer of mito-transferred naive CD4+ T cells from old mice into Rag1-KO mice protected mice against influenza A and Mycobacterium tuberculosis (M.tb) infections. These results open the possibility for future translational studies into the immunological and therapeutic implications of directed mito-transfer in aged lymphocytes to re-establish their loss of function.
