TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia
Navaeiseddighi, Z.; Guo, K.; Hasan, S. S.; Wang, Z.; Mishra, R.; Schmit, T.; Ahsan, J.; Moser, E. J.; Hur, J.; Yount, J. S.; Mathur, R.; Zhou, L.; Khan, N.
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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.
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