The overall objective of this project is to determine the physiological relevance of the NKG2D receptor in NK cell-mediated and T cell-mediated immune responses. In prior studies, we have implicated this receptor in NK cell-mediated anti-viral and anti-tumor immunity, and have uncovered an important role for NKG2D in the pathology associated with type I autoimmune diabetes. In this competitive renewal application, we will focus our efforts towards defining the mechanisms of NKG2D-dependent activation of T cells and NK cells in model systems of immunity to tumors and pathogens and in autoimmunity.
Specific aims are: 1. To determine the mechanisms whereby NKG2D and its ligands contribute to autoimmune diabetes in the NOD mouse model;2. To develop genetic models for selective deficiency of NKG2D in discrete cell lineages and to determine the effects on innate and adaptive immune responses;and, 3. To test the hypothesis that NKG2D costimulation in human and mouse T cells is restricted to unique T cell subsets or activation states.
Aim 1 wi|l evaluate the potential role for NKG2D in models of autoimmunity that are regulated by NK cells, CD8+ cells (e.g. the 8.3 TcR-transgenic model), and CD4+ T cells (e.g. the BDC2.5 TcR-transgenic model). In addition, we will test whether anti-NKG2D mAb treatment can affect autoimmune manifestations other than diabetes.
In aim 2 we will generate a conditionally NKG2D-deficient mouse on the C57BL/6 background in order to test the hypothesis that NKG2D is important in immunity against autoantigens, tumors and pathogens. An important goal is to determine in model systems where the function of NKG2D is critical --whether NKG2D is required in NK cells, T cells, or both cell types.
Specific aim 3 will determine why NKG2D is unable to costimulate freshly isolated human NKG2D+ T cells or short-term activated mouse NKG2D+ T cells, but is able to efficiently costimulate long-term cultured human and mouse CD8+ T cells and clones, as well as CD8+ T cells isolated from tissue undergoing an autoimmune reaction in vivo.

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 #
5R37AI066897-10
Application #
7767706
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Bourcier, Katarzyna
Project Start
2001-03-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
10
Fiscal Year
2010
Total Cost
$364,245
Indirect Cost
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Jensen, Helle; Chen, Shih-Yu; Folkersen, Lasse et al. (2017) EBI3 regulates the NK cell response to mouse cytomegalovirus infection. Proc Natl Acad Sci U S A 114:1625-1630
Mukherjee, Sayak; Jensen, Helle; Stewart, William et al. (2017) In silico modeling identifies CD45 as a regulator of IL-2 synergy in the NKG2D-mediated activation of immature human NK cells. Sci Signal 10:
Mukherjee, Sayak; Stewart, David; Stewart, William et al. (2017) Connecting the dots across time: reconstruction of single-cell signalling trajectories using time-stamped data. R Soc Open Sci 4:170811
Lam, Viola C; Lanier, Lewis L (2017) NK cells in host responses to viral infections. Curr Opin Immunol 44:43-51
Nabekura, Tsukasa; Gotthardt, Dagmar; Niizuma, Kouta et al. (2017) Cutting Edge: NKG2D Signaling Enhances NK Cell Responses but Alone Is Insufficient To Drive Expansion during Mouse Cytomegalovirus Infection. J Immunol 199:1567-1571
Jensen, Helle; Potempa, Marc; Gotthardt, Dagmar et al. (2017) Cutting Edge: IL-2-Induced Expression of the Amino Acid Transporters SLC1A5 and CD98 Is a Prerequisite for NKG2D-Mediated Activation of Human NK Cells. J Immunol 199:1967-1972
Crome, Sarah Q; Nguyen, Linh T; Lopez-Verges, Sandra et al. (2017) A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat Med 23:368-375
Morvan, Maelig G; Champsaur, Marine; Reizis, Boris et al. (2017) Chronic In Vivo Interaction of Dendritic Cells Expressing the Ligand Rae-1? with NK Cells Impacts NKG2D Expression and Function. Immunohorizons 1:10-19
Hosomi, Shuhei; Grootjans, Joep; Tschurtschenthaler, Markus et al. (2017) Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation. J Exp Med 214:2985-2997
Vadstrup, Kasper; Galsgaard, Elisabeth Douglas; Jensen, Helle et al. (2017) NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration. Exp Mol Pathol 103:56-70

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