Major histcompatibility complex (MHC) class I molecules present intracellular pathogen-derived peptides to T-cells, which become activated upon engagement of clonotypis alphabeta T-cell antigen receptors (TCRs) and of costimulatory receptors. Distant homologs of MHC class I molecules have altered functions and interact with different receptors and T-cell subsets. Among these are human MICA andMICB, which are cell stress-inducible surface molecules that are not associated with antigenic peptide or nonpeptide ligands. They have a limited expression in intestinal epithelium and epithelial tumors, can be potently induced in virus-infected cells, and are recognized as self-antigens by a subset of T-cells with gammadelta TCRs that is frequently enriched in epithelial sites. In addition, MICA/B function as ligands for an activating recepotr, NKG2D, which is broadly expressed on lymphocyte subsets. Engagement of NKG2Dcan trigger natural killer (NK) cells and augment responsesby antigen-specific CD8+ alphabeta T-cells and gammadelta T-cells. The here proposed research aims at advancingknowledge of this immunological system that may be capableof mobilizing diverse effector cells against tumor andvirus-infected cells. Studies planned under Specific Aim I will define the molecular mechanisms underlying the stress-inducible expression of the MICA/B genes. Transcriptionalinduction will be measured, relevant transcription factorsidentified, and their binding to predictable sites within adefined promoter context determined. Studies under Specific Aim II are designed to demonstrate interactions of MICA/Bwith gammadelta TCRs and to investigate how variable gammaand delta chains contribute to TCR specificity. Furthergoals are to quantify the subset of gammadelta T-cellsspecific for MICA/B and to determine the role of NKG2D inactivation. Studies under Specific Aims III will investigate the induction of MICA/B in cells infected by cytomegalovirus and the function of NKG2D in promoting virus-specific CD8+ alphabeta T-cell responses. This and additional experimental systems have been chosen to demonstrate that NKG2D can costimulate TCR-mediated T-cell activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AI030581-12
Application #
6326834
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Hackett, Charles J
Project Start
1991-07-01
Project End
2006-04-30
Budget Start
2001-06-01
Budget End
2002-04-30
Support Year
12
Fiscal Year
2001
Total Cost
$455,710
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
El-Gazzar, A; Cai, X; Reeves, R S et al. (2014) Effects on tumor development and metastatic dissemination by the NKG2D lymphocyte receptor expressed on cancer cells. Oncogene 33:4932-40
Benitez, Andrea Caballero; Dai, Zhenpeng; Mann, Henning H et al. (2011) Expression, signaling proficiency, and stimulatory function of the NKG2D lymphocyte receptor in human cancer cells. Proc Natl Acad Sci U S A 108:4081-6
Hanaoka, Nobuyoshi; Jabri, Bana; Dai, Zhenpeng et al. (2010) NKG2D initiates caspase-mediated CD3zeta degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease. J Immunol 185:5732-42
Dai, Zhenpeng; Turtle, Cameron J; Booth, Garrett C et al. (2009) Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus. J Exp Med 206:793-805
Venkataraman, Gopalakrishnan M; Suciu, Dominic; Groh, Veronika et al. (2007) Promoter region architecture and transcriptional regulation of the genes for the MHC class I-related chain A and B ligands of NKG2D. J Immunol 178:961-9
Azimi, Nazli; Jacobson, Steven; Tanaka, Yuetsu et al. (2006) Immunostimulation by induced expression of NKG2D and its MIC ligands in HTLV-1-associated neurologic disease. Immunogenetics 58:252-8
Groh, Veronika; Smythe, Kimberly; Dai, Zhenpeng et al. (2006) Fas-ligand-mediated paracrine T cell regulation by the receptor NKG2D in tumor immunity. Nat Immunol 7:755-62
Gonzalez, S; Groh, V; Spies, T (2006) Immunobiology of human NKG2D and its ligands. Curr Top Microbiol Immunol 298:121-38
Groh, Veronika; Li, Yongqing Q; Cioca, Daniel et al. (2005) Efficient cross-priming of tumor antigen-specific T cells by dendritic cells sensitized with diverse anti-MICA opsonized tumor cells. Proc Natl Acad Sci U S A 102:6461-6
Somersalo, Kristina; Anikeeva, Nadja; Sims, Tasha N et al. (2004) Cytotoxic T lymphocytes form an antigen-independent ring junction. J Clin Invest 113:49-57

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