Natural Killer (NK) cells are a component of the innate immune system. They play an important role in the defense against pathogens and tumors, and use a diverse pool of receptors to eliminate their targets. NK cell-mediated cytotoxicity is determined by a balance of signals (1) emanating from the recognition of “missing-self” (2) and “induced-self” on target cells. NK cells are best know for their detection of “missing-self”, which involves the activation of NK cells when they encounter cells with low or absent expression of major histocompatibility complex class I molecules. However, NK cells can also mediate the recognition of “induced-self”, or self-proteins upregulated in infected or transformed cells. Although many NK cell activating receptors have been proposed to mediate “induced-self” recognition, the exact ligands recognized remain in many cases unknown.
An exception to this is NKG2D, an invariant receptor shared by NK cells and T cells that can potently induce killing. NKG2D recognizes a family of “induced-self” ligands that has been extensively studied and remains a field of active investigation. This dissertation describes my efforts at gaining a better understanding of the effect of “induced-self” recognition by the NKG2D receptor on host immunity. First, using a transgenic mouse model, I discuss the effect of constitutive NKG2D ligand expression on global NK cell function. I show that NKG2D-independent functions are unaltered when NK cells are exposed to NKG2D ligands constitutively. Second, I describe a novel model created to selectively express the NKG2D ligand Rae-1 on targeted cell subsets and, in particular, on dendritic cells (DCs). I use this novel tool to investigate the role of NKG2D in the crosstalk between DCs and NK cells and CD8+ T cells. My studies suggest that the NKG2D pathway is dispensable for NK and CD8+ T cell activation by dendritic cells. Finally, I discuss a novel model developed to determine the role of soluble NKG2D ligands on NKG2D function. My studies suggest that soluble NKG2D ligands can potently impair NK cell function in the absence of any additional accelerating factors.
|Advisor:||Lanier, Lewis L.|
|Commitee:||Hanahan, Douglas, Seaman, William E.|
|School:||University of California, San Francisco|
|School Location:||United States -- California|
|Source:||DAI-B 71/08, Dissertation Abstracts International|
|Subjects:||Cellular biology, Microbiology|
|Keywords:||Cancer, NK cells, NKG2D, Rae-1|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be