The oyerajl^objective Of this project is to determine the physiological relevance of the NKG2D receptor in NK cell^mediated land T cellr^mediatcid 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 program, 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'Nk<32D and its ligands contribute to autoimmune diabetes in the NOD and EAE mouse model;2. To;deplop genetic models for selective deficiency of NKG2D in discrete cell lineages and to determine the effectS;pn 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 will evaluate the potiB'ntial role for NKG2D in models of autoimmunity that are regulated by NK cells, CD8+ cells, and CD4+ T cells In addition, we will test whether anti-NKG2D mAb treatment can affect autoimmune manifestations othel'than diabetes.
In aim 2 we will generate a conditionally NKG2D-deficient mouse on the C57BU6 bacltground in order to test the hypothesis that NKG2b 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.

Public Health Relevance

(See Instructions): NKG2D has been demonstrated to provide protective immunity against pathogens and tumors, as well as implicated in autoimmune diseases, including rheumatoid arthritis and type I diabetes. A better understanding of this immune receptor and its ligands may provide new therapeutic approaches for vaccination against tumors and microbial pathogens and for intervention in autoimmune diseases.

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 #
5R37AI066897-12
Application #
8225130
Study Section
Special Emphasis Panel (NSS)
Program Officer
Bourcier, Katarzyna
Project Start
2001-03-01
Project End
2016-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
12
Fiscal Year
2012
Total Cost
$386,250
Indirect Cost
$136,250
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
Cerwenka, Adelheid; Lanier, Lewis L (2016) Natural killer cell memory in infection, inflammation and cancer. Nat Rev Immunol 16:112-23
Lam, Viola C; Lanier, Lewis L (2016) NK cells in host responses to viral infections. Curr Opin Immunol 44:43-51
Hendricks, Deborah W; Min-Oo, Gundula; Lanier, Lewis L (2016) Sweet Is the Memory of Past Troubles: NK Cells Remember. Curr Top Microbiol Immunol 395:147-71
Morvan, Maelig G; Lanier, Lewis L (2016) NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer 16:7-19
Lanier, Lewis L (2015) NKG2D Receptor and Its Ligands in Host Defense. Cancer Immunol Res 3:575-82
O'Sullivan, Timothy E; Sun, Joseph C; Lanier, Lewis L (2015) Natural Killer Cell Memory. Immunity 43:634-45
Weinger, Jason G; Plaisted, Warren C; Maciejewski, Sonia M et al. (2014) Activating receptor NKG2D targets RAE-1-expressing allogeneic neural precursor cells in a viral model of multiple sclerosis. Stem Cells 32:2690-701
Lanier, Lewis L (2014) Of snowflakes and natural killer cell subsets. Nat Biotechnol 32:140-2
Crane, Courtney A; Austgen, Kathryn; Haberthur, Kristen et al. (2014) Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci U S A 111:12823-8
Beaulieu, Aimee M; Bezman, Natalie A; Lee, Jang Eun et al. (2013) MicroRNA function in NK-cell biology. Immunol Rev 253:40-52

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