The failure of the trophoblast to express MHC class II antigens is believed to be essential for survival of the fetus during pregnancy. It is therefore likely that strong evolutionary pressures to preserve reproduction would develop tight overlapping regulatory controls. We have identified two such control mechanisms which inhibit trophoblast class II expression. An upstream negative regulatory element (IAalphaNRE) in the promoter of the murine class II IAalpha gene that represses transcription specifically in trophoblasts. In addition, the class II transcription activator (CIITA), the master regulator of class II expression is not transcribed in trophoblast cells, nor can it be induced by IFN-gamma or other cytokines that upregulate class II in most other cell types. The goals of this grant are to further define the underlying mechanisms responsible for the inability of the trophoblast to express class II and the physiological relevance of this to fetal persistence. Hopefully, these studies will also elucidate fundamental control mechanisms for class II expression that have application to other areas of clinical relevance such as cancer and autoimmunity.

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Human Embryology and Development Subcommittee 1 (HED)
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Hewitt, Tyl
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Roswell Park Cancer Institute Corp
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Tomasi, Thomas B; Magner, William J; Wiesen, Jennifer L et al. (2010) MHC class II regulation by epigenetic agents and microRNAs. Immunol Res 46:45-58
Wiesen, Jennifer L; Tomasi, Thomas B (2009) Dicer is regulated by cellular stresses and interferons. Mol Immunol 46:1222-8
Gregorie, Christopher J; Wiesen, Jennifer L; Magner, William J et al. (2009) Restoration of immune response gene induction in trophoblast tumor cells associated with cellular senescence. J Reprod Immunol 81:25-33
Asirvatham, Ananthi J; Magner, William J; Tomasi, Thomas B (2009) miRNA regulation of cytokine genes. Cytokine 45:58-69
Asirvatham, Ananthi J; Gregorie, Christopher J; Hu, Zihua et al. (2008) MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components. Mol Immunol 45:1995-2006
Khan, A Nazmul H; Tomasi, Thomas B (2008) Histone deacetylase regulation of immune gene expression in tumor cells. Immunol Res 40:164-78
Khan, A Nazmul H; Gregorie, Christopher J; Tomasi, Thomas B (2008) Histone deacetylase inhibitors induce TAP, LMP, Tapasin genes and MHC class I antigen presentation by melanoma cells. Cancer Immunol Immunother 57:647-54
Chou, Shiuh-Dih; Tomasi, Thomas B (2008) Spatial distribution of histone methylation during MHC class II expression. Mol Immunol 45:971-80
Khan, A Nazmul H; Magner, William J; Tomasi, Thomas B (2007) An epigenetic vaccine model active in the prevention and treatment of melanoma. J Transl Med 5:64
Shang, Limin; Tomasi, Thomas B (2006) The heat shock protein 90-CDC37 chaperone complex is required for signaling by types I and II interferons. J Biol Chem 281:1876-84

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