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CD4+ T-cell response to mitochondrial cytochrome B in human melanoma
Kui Shin Voo1, Gang Zeng, Jian-Bing Mu
1The Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, Houston, Texas, USA.
Abstract:
Mitochondrial DNA (mtDNA) is highly susceptible to mutations due to the low level of DNA repair and the presence of a high level of reactive oxygen species in the organelle. Although mtDNA mutations have been implicated in degenerating diseases, aging, and cancer, very little is known about the role of T cells in immunosurveillance for mtDNA aberrations. Here, we describe T-cell recognition of a peptide translated from an alternative open reading frame of the mitochondrial cytochrome b (cyt b) gene in melanoma cells established from a patient. To understand how the cyt b gene is transcribed and translated in tumor cells, we found that cyt b-specific CD4(+) T cells only recognized protein fractions derived from cytoplasm and not from mitochondria. However, T-cell recognition of tumor cells could be inhibited by treatment of tumor cells with rhodamine 6G inhibitor, which depletes mitochondria. These findings suggest that cyt b mRNA is leaked out of the mitochondria and then translated in the cytoplasm for presentation to CD4(+) T cells. The cyt b cDNAs from this patient contain highly heteroplasmic transition mutations compared with control cell lines, suggesting a compromise of mitochondrial integrity that may have contributed to melanoma induction or progression. These findings provide the first example of a mitochondrial immune target for CD4(+) T cells and therefore have implications for the immunosurveillance of mitochondrial aberrations in cancer patients.
Insights
T cells can recognize peptides from mitochondrial DNA (mtDNA) mutations in melanoma. This suggests a new way the immune system may detect mitochondrial damage in cancer.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Mitochondrial DNA (mtDNA) mutations are linked to diseases, aging, and cancer.
- The role of T cells in detecting mtDNA aberrations is poorly understood.
- Mitochondria are crucial for cellular energy but also produce reactive oxygen species, increasing mutation risk.
Purpose of the Study:
- To investigate T-cell recognition of peptides derived from mitochondrial genes in melanoma.
- To explore the mechanism of presentation of mitochondrial antigens to T cells.
- To determine if mitochondrial aberrations are recognized by the immune system in cancer.
Main Methods:
- Analysis of T-cell recognition of melanoma cell protein fractions.
- Investigation of cytochrome b (cyt b) gene transcription and translation.
- Inhibition studies using rhodamine 6G to deplete mitochondria.
- Sequencing of cyt b cDNAs to identify mutations.
Main Results:
- CD4(+) T cells recognized a peptide translated from an alternative open reading frame of the mitochondrial cytochrome b (cyt b) gene.
- T-cell recognition occurred with protein fractions from the cytoplasm, not mitochondria.
- Mitochondrial depletion inhibited T-cell recognition, suggesting cytoplasmic translation of leaked mitochondrial mRNA.
- Melanoma patient's cyt b cDNAs showed heteroplasmic mutations, indicating compromised mitochondrial integrity.
Conclusions:
- This study identifies a novel mitochondrial immune target for CD4(+) T cells.
- Mitochondrial mRNA may be translated in the cytoplasm for presentation to T cells.
- These findings have implications for cancer immunosurveillance of mitochondrial aberrations.
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