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Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2010)

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 emanating from the recognition of "missing-self" 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.

    Cover page: Effects of NKG2D ligand expression on host immune responses
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2017)
    To investigate how dendritic cells (DCs) interact with NK cells in vivo, we developed a novel mouse model in which Rae-1ε, a ligand of the NKG2D receptor, is expressed in cells with high levels of CD11c. In these CD11c-Rae1 mice, expression of Rae-1 was confirmed on all subsets of DCs and a small subset of B and T cells, but not on NK cells. DC numbers and activation status were unchanged, and NK cells in these CD11c-Rae1 mice presented the same Ly49 repertoire and maturation levels as their littermate wildtype controls. Early NK cell activation after mouse CMV infection was slightly lower than in wildtype mice, but NK cell expansion and viral control were comparable. Notably, we demonstrate that chronic interaction of NK cells with NKG2D ligand-expressing DCs leads to a reversible NKG2D down-modulation, as well as impaired NKG2D-dependent NK cell functions, including tumor rejection. In addition to generating a useful mouse model, our studies reveal in vivo the functional importance of the NK cell and DC cross-talk.
      Cover page: Chronic In Vivo Interaction of Dendritic Cells Expressing the Ligand Rae-1ε with NK Cells Impacts NKG2D Expression and Function
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2012)
      NK cells have been shown to either promote or protect from autoimmune diseases. Several studies have examined the role of receptors preferentially expressed by NK cells in the spontaneous disease of NOD mice or the direct role of NK cells in acute induced disease models of diabetes. Yet, the role of NK cells in spontaneous diabetes has not been directly addressed. Here, we used the NOD.NK1.1 congenic mouse model to examine the role of NK cells in spontaneous diabetes. Significant numbers of NK cells were only seen in the pancreas of mice with disease. Pancreatic NK cells displayed an activated surface phenotype and proliferated more than NK cells from other tissues in the diseased mice. Nonetheless, depletion of NK cells had no effect on dendritic cell maturation or T cell proliferation. In spontaneous disease, the deletion of NK cells had no significant impact on disease onset. NK cells were also not required to promote disease induced by adoptively transferred pathogenic CD4(+) T cells. Thus, NK cells are not required for spontaneous autoimmune diabetes in NOD mice.
        Cover page: NK Cells Are Not Required for Spontaneous Autoimmune Diabetes in NOD Mice
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