TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia

During respiratory virus infections, CD8 T cells kill virus-infected cells and establish antigen-specific immune memory, but excessive or dysregulated responses can also contribute to lung immunopathology. The development and maintenance of optimal CD8 T cell effector and memory responses depend on mitochondrial fitness, which can be compromised across multiple physiologic and pathologic conditions. However, how impaired mitochondrial fitness affect antiviral CD8 T cell responses remains poorly understood. Here, we used a CD8 T cell-specific TFAM-haploinsufficient mouse model to induce moderate mitochondrial stress without the severe mitochondrial dysfunction associated with complete TFAM loss, providing a genetically controlled model of mitochondrial perturbations relevant to physiologic conditions. TFAM insufficiency disrupted mitochondrial integrity and cellular bioenergetics and increased mitochondrial DNA and oxidative stress in CD8 T cells. During primary influenza A virus (IAV) infection, TFAM-insufficient CD8 T cells exhibited heightened cytotoxic activity and inflammatory responses associated with lung immunopathology, followed by progressive functional exhaustion, diminished antigen-specific responses, and impaired protective immunity. Consistent with the physiologic relevance of these findings, CD8 T cells from older individuals exhibited reduced TFAM expression and mitochondrial function. Collectively, our findings demonstrate that moderate mitochondrial stress can alter the trajectory of antiviral CD8 T cell responses, promoting pathogenic effector activity during acute infection while compromising subsequent protective immunity.