Interferon‐γ rescues HLA class Ia cell surface expression in term villous trophoblast cells by inducing synthesis of TAP proteins

Abstract Human placental trophoblast cells that constitute the materno‐fetal interface during pregnancy escape maternal alloimmune attack. The different trophoblast cell subpopulations have developed efficient regulatory mechanisms to prevent expression of β2‐microglobulin‐associated HLA class Ia molecules at their cell surface. We previously reported the presence of HLA class Ia messages in villous cytotrophoblast cells and in the syncytiotrophoblast differentiated in vitro purified from term placenta. In this study, we found that these transcripts are translated in heavy chain proteins that are endoglycosidase H sensitive and thus retained in the endoplasmic reticulum or cis ‐Golgi. Moreover, these class Ia heavy chains can be co‐immunoprecipitated with the chaperone protein calnexin resident in the endoplasmic reticulum. When these trophoblast cells are treated with interferon (IFN)‐γ, part of the class Ia heavy chains become endoglycosidase H resistant, demonstrating that they have left the endoplasmic reticulum. Furthermore, after such a treatment, these heavy chains are detectable at the cell surface of these trophoblast cells, as assessed by two‐color flow cytometry analysis and immunoprecipitation of cell surface biotinylated proteins using the W6/32 anti‐HLA class I monoclonal antibody (mAb). IFN‐γ treatment induces a significant enhancement of the transcription of transporters associated with antigen processing (TAP1 and TAP2) rather than an increase of HLA class I or β2‐microglobulin messages. Finally, we demonstrate that an anti‐TAP1 mAb coimmunoprecipitates TAP1 proteins and HLA class Ia heavy chains in these IFN‐γ‐treated trophoblast cells. Thus, the constitutive absence of HLA class Ia cell surface expression in term villous cytotrophoblast and syncytiotrophoblast is likely to be due to a lack of transporter proteins that participate in the proper assembly of these molecules in the endoplasmic reticulum. Such a defect can be modified upon IFN‐γ treatment.