TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia
Abstract
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.
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BibTeX
@misc{navaeiseddighi2026tfam,
title = {{TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia}},
author = {Zahrasadat Navaeiseddighi and Kai Guo and Syed Shafat Hasan and Zhihan Wang and Rutuparnna Mishra and Taylor Schmit and Jamanah Ahsan and Emily J Moser and Junguk Hur and Jacob S. Yount and Ramkumar Mathur and Liang Zhou and Nadeem Khan},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754254},
url = {https://doi.org/10.64898/2026.09.24.754254},
note = {CC BY-NC 4.0},
}
RIS
TY - UNPB
TI - TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia
AU - Zahrasadat Navaeiseddighi
AU - Kai Guo
AU - Syed Shafat Hasan
AU - Zhihan Wang
AU - Rutuparnna Mishra
AU - Taylor Schmit
AU - Jamanah Ahsan
AU - Emily J Moser
AU - Junguk Hur
AU - Jacob S. Yount
AU - Ramkumar Mathur
AU - Liang Zhou
AU - Nadeem Khan
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754254
UR - https://doi.org/10.64898/2026.09.24.754254
AB - 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.
SN - 2692-8205
ER -