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a Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5
b Department of Obstetrics and Gynaecology and
c Department of Molecular and Medical Genetics, Universityof Toronto, Toronto, Ontario, Canada M5G 1X5
d Department of Stomatology and
e Departments of Anatomy, Pharmaceutical Chemistry, and Obstetrics, Gynecologyand Reproductive Sciences, University of California San Francisco, San Francisco, California 94143
Human maternal tolerance to a semiallogenic fetus may be maintained, in part, by the unusual expression pattern of antigen-presenting molecules in placental trophoblast cells. Extravillous cytotrophoblast (EVC) cells, which invade the maternal decidua, express high levels of human leukocyte antigen G (HLA-G), a nonclassical, major histocompatibility complex (MHC) class I molecule. HLA-G transcripts have been detected in tumors and other tissues, yet protein accumulation is rare. We show that, within EVC cells themselves, the mRNA is more broadly expressed than the protein. Specifically, accumulation of HLA-G protein was markedly delayed during EVC cell differentiation. To elucidate this mechanism, we performed a comprehensive analysis comparing the expression of HLA-G and proteins essential for MHC class I expression at the cell surface. The transporter for antigen processing proteins TAP1 and TAP2, as well as tapasin and ß2-microglobulin, appeared to be coordinately expressed throughout EVC cell columns. Strikingly, they all accumulated well in advance of the HLA-G protein but concurrently with its mRNA. A similar delay in the accumulation of the HLA-G protein was observed in vitro, using cultures of chorionic villi. We conclude that posttranscriptional regulation of HLA-G is fundamental to EVC cell development and is achieved independently of the peptide loading system. This represents a novel mechanism of MHC class I regulation.
1 This work is supported by a grant from the Medical Research Council of Canada to J.C.C. J.C. is a Research Fellow and J.C.C. a Scholar of the MRC Canada.
2 Correspondence: James C. Cross, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5. FAX: 416 586 8588; cross{at}mshri.on.ca
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