PROGRESS REPORT AND PRELIMINARY RESULTS? I. Synopsis of Research Area at the Onset of the Funding Period? Prior to the current funding period, our laboratory had established that human MICA, and MICB,? two closely related glycoproteins that are distant homologs of MHC class I, function as strcss-inducible? surface molecules that are not associated with p2-microglobulin(fl^m) and antigenic pepiide or tion-? peptide ligands and have a restricted tissue distribution in variable areas of gastrointestinalepithelium.? However, expression of MIC is potently induced by cytomegalovirus (CMV) infection of ftbroblast and? endothelial cells and is frequently associated with epithelial tumors including breast, lung, gjsiric, colon,? renal, ovarian and prostate carcinoma, and melanoma. MIC are recognized by Vhl v6 T cells, which? represent a small subset of y& T cells that are enriched in epithelialsites, mainly in intestinal epithelium? as well as in epithelial tumors. In addition, MIC function as ligands of the NKG2D--DAP10 receptor? complex, which strongly activates NK cells and stimulates responses by antigen-specific CDS c/.(3 T cells? and 76 T cells. Thus, the induced expression of MiC by adverse cellular or environmental conditions,? such as malignancies and infection, may enable the immune system to rapidly mobilbe protective? effector cell functions. The regulatory mechanism facilitating MIC induction may be associated with? putative heat-shock elements (HSEs) in the 5'-end upstream regions of the corresponding .<*enes. These? prototypic transcription inducer sites are characteristic of heat shockprotein 70 (HSP70) genes a:id bind? activated trimeric HSF1. In aggregate, the functional and molecular evidence of the NHC--NKG2D? system supported a model of ''induced self complementing the well established ''missing self? recognition that is represented by conventional MHC class I molecules and their interactions with arrays? of inhibitory NK cell receptors.?
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