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CD4⁺ T-Cell Response to Mitochondrial Cytochrome b in Human Melanoma

¹ The Center for Cell and Gene Therapy and ² Department of Immunology, Baylor College of Medicine, Houston, Texas; ³ Division of Urologic Oncology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California; and ⁴ Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases; and ⁵ Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Rong-Fu Wang, The Center for Cell and Gene Therapy, Baylor College of Medicine, Alkek Building, N1120, One Baylor Plaza, Houston, TX 77030. Phone: 713-798-1244; Fax: 713-798-1263; E-mail: rongfuw{at}bcm.tmc.edu.

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. (Cancer Res 2006; 66(11): 5919-26)

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