Mitochondrial Transcription Factor A Deficiency in T Cells Leads to Activation of the Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase/Stimulator of Interferon Genes Pathway and Production of Autoantibodies in Mice

Mitochondrial transcription factor A (TFAM) is a key regulator of mitochondrial DNA transcription and replication. T cell‐specific TFAM‐deficient mice are immunocompromised, often succumbing to viral infection, and their T cells are unresponsive to T‐cell antigen receptor (TCR) stimulation, suggesting that TFAM‐mediated mitochondrial activity regulates T‐cell activity, such as effector function and memory formation. In contrast to the attenuation of immune response, TFAM deficiency may also induce inflammatory responses, raising the possibility that TFAM deficiency results in inflammation‐mediated autoimmune responses. Thus, besides regulating T‐cell function, TFAM plays important roles in autoimmune responses. However, its role in autoimmune diseases remains uncertain. We aimed to investigate the role of TFAM in autoimmune diseases using T cell‐specific TFAM‐deficient mice. We detected anti‐double‐strand (ds) DNA antibody, and interferon alpha (IFNα) and IFNγ in the serum of TFAM fl/fl CD4Cre mice after 30 weeks of age. Mononuclear cell infiltration was observed in the kidneys. TFAM‐deficient T cells exhibited leakage of mitochondrial DNA into the cytoplasm. Cytoplasmic mitochondrial DNA was associated with activation of TANK‐binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3)—the downstream molecules of the nucleic acid sensor cyclic guanosine monophosphate–adenosine monophosphate synthase/stimulator of IFN genes (cGAS/STING) machinery. mRNA expression of type I IFN genes was elevated in T cells from TFAM fl/fl CD4Cre mice. The suppressive function of Foxp3 + regulatory T (Treg) cells, which play a major role in establishment of peripheral tolerance, was reduced in the absence of TFAM. Our findings suggest that T cells in TFAM‐deficient conditions may contribute to immune instability and autoimmune responses by inducing type I IFN‐mediated inflammatory responses.