Cell-Stress Induced Immune Responses

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

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