CD4+ T-cell response to mitochondrial cytochrome B in human melanoma.
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.
Voo
Kui Shin
KS
The Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, Houston, Texas, USA.
Zeng
Gang
G
Mu
Jian-Bing
JB
Zhou
Juhua
J
Su
Xin-Zhuan
XZ
Wang
Rong-Fu
RF
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
D004272:DNA, Mitochondrial; D018984:Epitopes, T-Lymphocyte; D015798:HLA-DR1 Antigen; D045303:Cytochromes b