The oyerajl^objective Of this project is to determine the physiological relevance of the NKG2D receptor in NKcell^mediated land T cellr^mediatcid immune responses. In prior studies, we have implicated this receptor inNK cell-mediated anti-viral and anti-tumor immunity, and have uncovered an important role for NKG2D in thepathology associated with type I autoimmune diabetes. In this program, we will focus our efforts towardsdefining the mechanisms of NKG2D-dependent activation of T cells and NK cells in model systems ofimmunity to tumors and pathogens and in autoimmunity.
Specific aims are: 1. To determine the mechanismswhereby'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 theeffectS;pn innate and adaptive immune responses; and, 3. To test the hypothesis that NKG2D costimulationin: human and mouse T cells is restricted to unique T cell subsets or activation states.
Aim 1 will evaluate thepotiB'ntial role for NKG2D in models of autoimmunity that are regulated by NK cells, CD8+ cells, and CD4+ Tcells In addition, we will test whether anti-NKG2D mAb treatment can affect autoimmune manifestationsothel' than diabetes.
In aim 2 we will generate a conditionally NKG2D-deficient mouse on the C57BU6bacltground 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 iscritical -whether NKG2D is required in NK cells, T cells, or both cell types.
Specific aim 3 will determine whyNKG2D is unable to costimulate freshly isolated human NKG2D-'- T cells or short-term activated mouseNKG2D+ T cells, but is able to efficiently costimulate long-term cultured human and mouse CD8+ T cells andclones, as well as CD8+ T cells isolated from tissue undergoing an autoimmune reaction in vivo.
(See Instructions):NKG2D has been demonstrated to provide protective immunity against pathogens and tumors, as well asimplicated in autoimmune diseases, including rheumatoid arthritis and type I diabetes. A betterunderstanding of this immune receptor and its ligands may provide new therapeutic approaches forvaccination against tumors and microbial pathogens and for intervention in autoimmune diseases.
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