The failure of the trophoblast to express MHC 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 of these genes. We have shown that in trophoblasts, class II expression is mediated by at least two control mechanisms involving repression of class II transactivator transcription and an upstream negative regulatory element [NRE]. Fusion of B cells expressing class II with trophoblast cells has been reported to result in silencing of the CIITA gene in the heterokaryon suggesting a repressor in the trophoblast. Repression of class II in trophoblast cells has been postulated to result from several candidate inhibitors of CIITA transcription [Blimp-1, TGF-beta]. We have demonstrated that low concentrations of deacetylase inhibitors [DAIs] activate class II and costimulatory molecules on trophoblast cells without demonstrable CIITA. DAIs at higher concentrations induce cell cycle blocks and apoptotic cells expressing class II, CD4O, CD8O and CD86. This grant will explore the possibility of a CIITA independent pathway of class II activation mediated by epigenetic agents, such as acetylation and methylation, in trophoblast cells and attempt to further define the underlying molecular pathways. The physiological relevance of these findings to the ability of the fetal trophoblast cells to initiate an immune response will be investigated. The expression of MHC and other key immune genes will be evaluated on apoptotic trophoblast cells produced by DAIs and similar other toxic agents and on exosome derived trophoblast cell lines and on fresh murine trophoblast cells. Hopefully, these studies will enhance our understanding of the general mechanisms that regulate class II expression and certain other immune genes on trophoblast cells. This work may also have application to areas of clinical relevance, such as abortion, autoimmunity and cancer.
| 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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