title: CD4+ T-cell response to mitochondrial cytochrome B in human melanoma.
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.
authors.affiliation: The Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Kui Shin
authors.initials: KS
authors.lastname: Voo
authors.forename: Gang
authors.initials: G
authors.lastname: Zeng
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Mu
authors.forename: Juhua
authors.initials: J
authors.lastname: Zhou
authors.forename: Xin-Zhuan
authors.initials: XZ
authors.lastname: Su
authors.forename: Rong-Fu
authors.initials: RF
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045303:Cytochromes b / Q000235:genetics* / Q000276:immunology*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D015798:HLA-DR1 Antigen / Q000276:immunology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D008928:Mitochondria / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames
chemical_list: D004272:DNA, Mitochondrial; D018984:Epitopes, T-Lymphocyte; D015798:HLA-DR1 Antigen; D045303:Cytochromes b