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Reduced expression of mitochondrial transcription factor A (TFAM) in CD8⁺ T cells drives senescence-associated inflammatory lung injury during respiratory viral infection

ABSTRACT: Aging leads to dysregulated immune responses that worsen the severity of respiratory viral infections. As part of this dysfunction, CD8⁺ T cells exhibit altered inflammatory regulation, contributing both to viral clearance and to adverse lung injury. However, the cell-intrinsic mechanisms driving age-associated shifts in CD8⁺ T cell function remain poorly understood. Analysis of mouse and human single-cell datasets reveals that reduced expression of mitochondrial transcription factor A (TFAM) is a conserved feature of aging and acute viral illness, correlating with heightened inflammatory programs in CD8⁺ T cells. To define the functional consequences of this decline, we generated a CD8⁺ T cell–specific TFAM haploinsufficient mouse model (TFAM⁺/⁻) that recapitulates the physiological reduction of TFAM observed in aged human CD8⁺ T cells. We show that reduced TFAM expression is sufficient to disrupt mitochondrial integrity, activate mitochondrial DNA stress pathways, and prime CD8⁺ T cells toward a senescence-like state at homeostasis. During influenza infection, TFAM-insufficient CD8⁺ T cells mount an exaggerated early hyper-cytotoxic effector response and rapidly acquire exhaustion features. Despite adequate viral clearance, TFAM⁺/⁻ mice exhibit sustained inflammatory lung injury. Together, these findings demonstrate that aging-like TFAM insufficiency reprograms CD8⁺ T cell behavior through mitochondrial dysfunction, driving early inflammatory hyperactivation, premature exhaustion, and persistent lung immunopathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE317544 | GEO | 2026/02/02

REPOSITORIES: GEO

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Tfam-deficiency mediated mitochondrial disorder affects Langerhans cell maintenance and function

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Reduced expression of mitochondrial transcription factor A (TFAM) in CD8⁺ T cells drives senescence-associated inflammatory lung injury during respiratory viral infection

Project description:Reduced expression of mitochondrial transcription factor A (TFAM) in CD8⁺ T cells drives senescence-associated inflammatory lung injury during respiratory viral infection

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