TFAM deficiency in T cells worsens viral lung pathology and weakens immunity

In a preprint examining human cells and mice, researchers investigated how mitochondrial transcription factor A, or TFAM, shapes CD8+ T cell responses during influenza infection. Human CD8+ T cells showed an age-associated decline in TFAM expression and mitochondrial function. To model this loss, the team generated CD8+ T cell-specific TFAM-haploinsufficient mice. TFAM insufficiency damaged mitochondrial integrity and bioenergetics while increasing mitochondrial DNA and oxidative stress. During influenza challenge, TFAM-deficient CD8+ T cells produced excessive cytotoxic and inflammatory activity, causing lung immunopathology without clearing the virus better. This initial surge was followed by lost effector function, reduced antigen-specific responses, weaker protection after adoptive transfer, and impaired heterosubtypic recall immunity.