: Lymphocyte activation can be modulated by diverse inhibitory or activating receptors that were originally defined as natural killer (NK) cell receptors. Most commonly, these are triggered by interaction with major histocompatibility complex (MHC) class I molecules, which are ubiquitously expressed and serve as positive indicators for the integrity of cells. A notable exception is the activating NKG2D receptor, which is expressed on NK cells, alpha beta T cells and CD8 gamma delta T cells and interacts with inducible MIC molecules that serve as indicators of cellular distress. MIC are frequently expressed on epithelial tumors and are induced by cytomegalovirus (CMV) and mycobacterial infection. Engagement of NKG2D potently augments antigen-specific effector T cell responses and stimulates cytokine production and T cell proliferation. NKG2D is thus functionally equal to the classical costimulatory CD28 receptor, which interacts with ligands that are restricted to professional antigen-presenting cells. Hence, in aggregate, current evidence indicates that NKG2D and its ligands facilitate emergency responses that are triggered by physiological danger. The goals of this application are to further define the scope and medical significance of this system and to explore closely related research opportunities. Studies planned under Specific Aim I will examine the role of NKG2D in T cell responses against Herpes Simplex Virus (HSV) and investigate whether interactions of a specific CMV protein with MIC and a second set of NKG2D ligands may promote viral escape from T cell control. Studies under Specific Aim II will investigate the mechanism and the functional consequences of ligand-induced down modulation of NKG2D, which may prevent chronic and autoreactive T cell stimulation but may also cause an immunocompromised condition. Studies under Specific Aim III are designed to isolate and functionally characterize a novel costimulatory receptor, which is present on B cells, activated T cells and dendritic cells, and to identify its ligands.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Miller, Lara R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Hamada, Satoru; Caballero-Benitez, Andrea; Duran, Kate L et al. (2017) Soluble MICB in Plasma and Urine Explains Population Expansions of NKG2D+CD4 T Cells Inpatients with Juvenile-Onset Systemic Lupus Erythematosus. Open J Immunol 7:1-17
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
Tang, Fangming; Chen, Zhangguo; Ciszewski, Cezary et al. (2009) Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15. J Exp Med 206:707-19
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
Groh, Veronika; Bruhl, Anja; El-Gabalawy, Hani et al. (2003) Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci U S A 100:9452-7

Showing the most recent 10 out of 11 publications