Date of Award

2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Taku Kambayashi

Abstract

NK cells are part of the innate immune system, and play an important role in viral and tumor defense. Improving natural killer (NK) cell function could be beneficial for enhancing anti-tumor or anti-viral responses. However, efforts to improve NK cell function by disrupting negative regulators that target proximal signaling pathways paradoxically results in less responsive NK cells. This is often attributed to their ability to tune their responsiveness. In this thesis, I found that NK cells are extremely sensitive to loss of inhibitory ligand or mediators of inhibitory signaling. Using adoptive transfer and mixed chimera models, I found that MHC class I expression is necessary both in cis and trans for NK cells to possess full functionality. Furthermore, using an acute model of genetic targeting, I found that temporal ablation of SHP-1 was sufficient to drive hyporesponsiveness, and the loss of even a single allele of SHP-1 had profound effects on NK cell responses. However, the data also showed that tuned NK cells could still be stimulated to respond via analogs of secondary messengers of signaling, suggesting that NK cell tuning targets proximal signaling pathways.

To improve NK cell function but avoid NK cell tuning, I targeted a distal negative regulator of signaling. I found that genetic deletion of diacylglycerol kinase zeta (DGKζ), a negative regulator of diacylglycerol-mediated signaling, enhances NK cell function due to its distal position in the signaling cascade. Upon activating receptor stimulation, NK cells from mice lacking DGKζ display increased cytokine production and cytotoxicity in an ERK-dependent manner. This enhancement of NK cell function is NK cell-intrinsic and developmentally independent. Importantly, DGKζ deficiency does not affect inhibitory NK cell receptor expression or function. Thus, DGKζ KO mice display enhanced clearance of a TAP-deficient tumor. I therefore propose that enzymes that negatively regulate distal signaling pathways such as DGKζ represent novel targets for augmenting the therapeutic potential of NK cells.

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