Regulation Of Natural Killer Cell Development And Function By Activating Receptor Signaling Pathways

Natural killer (NK) cells are lymphocytes of the innate immune system that recognize and eliminate virally infected and transformed cells through their release of cytotoxic granules and production of inflammatory cytokines. The balance of intracellular signals received through NK cell activating and inhibitory receptors dictates these functions and generates target cell specificity during development. Many signaling pathways downstream of activating receptors contribute to these processes, however, what pathways and what signaling proteins contribute to NK cell development and function are not fully understood While NK cells do not possess an antigen-specific immunoreceptor, they do express a variety of germline-encoded activating and inhibitory receptors. MHC I-binding inhibitory receptors, including those of the Ly49 and KIR families, are expressed in a variegated manner, which creates ligand-specific diversity within the NK cell pool. In this thesis, I demonstrate that signals derived from activating receptors are critical for induction of Ly49 receptors/KIRs during NK cell development; activation signals through SLP-76 increased the probability of the Ly49 bi-directional Pro1 promoter to transcribe in the forward versus the reverse direction, leading to stable Ly49 receptor expression and receptor diversity in mature NK cells. Not only does activation through SLP-76 impact NK cell development, but downstream signaling pathways also impact NK cell function. Sustained Ca2+ signaling, known as store-operated Ca2+ entry (SOCE), occurs downstream of NK cell activating receptor engagement. CD8+ T cells require SOCE for cytokine production and cytotoxicity; however, less is known about its role in NK cells. In this thesis, I use mice deficient in STIM1/2, which are required for SOCE, to examine the contribution of sustained Ca2+ signaling to NK cell function. Surprisingly, we found that while SOCE is required for NK cell IFNγ production in an NFAT-dependent manner, NK cell degranulation and tumor rejection in vivo remained intact in the absence of SOCE. Our data suggest that mouse NK cells utilize different signaling mechanisms for cytotoxicity compared to other cytotoxic lymphocytes. In summary, NK cell activating receptor signals and downstream signaling pathways contribute greatly to the development and function of NK cells, allowing them to effectively eliminate cancer and virally infected cells.