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Researchers found that mitochondrial transcription factor A (TFAM) plays a critical role in regulating CD8 T cell function during influenza infection. When TFAM levels were reduced in mice, their CD8 T cells initially showed excessive inflammatory activity that caused lung tissue damage without improving viral clearance, then later exhibited impaired long-term immune memory. Human CD8 T cells showed age-related decline in TFAM expression and mitochondrial function, suggesting this mechanism may contribute to weakened immune responses in older adults.
Why it matters
This discovery could help explain why older individuals often experience more severe outcomes from respiratory infections and may point toward therapeutic strategies that support mitochondrial health to improve immune function and vaccine responses in aging populations.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
During respiratory virus infection, CD8 T cells kill infected cells and establish antigen-specific memory, but mechanisms regulating these functions remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM)-dependent mitochondrial fitness as a regulator of CD8 T cell function during influenza infection. Human CD8 T cells exhibited an age-associated decline in TFAM expression and mitochondrial function. To model this physiologically relevant decline and determine its consequences for antiviral immunity, we generated CD8 T cell-specific TFAM-haploinsufficient mice. TFAM insufficiency disrupted mitochondrial integrity and bioenergetics and increased mitochondrial DNA and oxidative stress. During influenza infection, TFAM-insufficient CD8 T cells exhibited increased cytotoxic and inflammatory activity associated with lung immunopathology without improved viral control. This early phenotype was followed by loss of effector function, diminished antigen-specific responses, reduced protection following adoptive transfer, and impaired heterosubtypic recall immunity. Thus, TFAM-dependent mitochondrial fitness is a cell-intrinsic regulator that limits immunopathology while sustaining recall immunity.