Characterization of lineage-specific expression and signaling function of mouse NKR-P1 (CD161).
Published: 2004
Language: eng
Number of pages: 183
Description: Furthermore, although it is known that the NK1.1 marker is encoded by the Nkrp1c gene, its transcriptional regulation has not been elucidated. The results presented in this thesis define the molecular basis of Nkrp1c expression in NK lineage cells. In particular, the location of the Nkrp1c transcriptional initiation site, a novel 5' untranslated exon, and the minimal functional core promoter have been identified. Furthermore, we describe the detection and analysis of a DNaseI hypersensitive site (HS1), located 9 kb upstream of the transcriptional initiation site, which exhibits NK cell-specific enhancer-like activity. Taken together, our findings identify the minimal elements necessary for conferring NK cell lineage-specific expression of the Nkrp1c gene. These findings set the stage for the further characterization of the DNA-binding factors responsible for the expression of this and other NK-specific genes, shedding light on our understanding of how NK cell functions are regulated.For over fifteen years, surface expression of the NK1.1 marker has been used to identify all cells belonging to a specific subset of lymphocytes, defining them as natural killer (NK) cells. NK1.1 epitope is shared by two closely related, but functionally opposing NK cell receptors, the stimulatory NKR-P1C and inhibitory NKR-P1B gene products. Thus, the molecular basis of NKR-P1B/C signaling in NK cells was investigated. In particular, the tyrosine kinase, Lck, was identified as the initiator of signaling for both the stimulatory and inhibitory NKR-P1 receptors. Furthermore, the amino acid motif (CxCP) was shown to mediate Lck association to the receptors, as well as the inhibitory motif (LxYxxL) responsible for their divergent functions. Most strikingly, the Lck tyrosine kinase is required for NKR-P1 activation, as NK cells from Lck-deficient mice cannot mediate NKR-P1-directed killing. Importantly, this discovery represents the first NK cell defect reported in these mice. These findings provide the foundation for a sequential model to explain the opposing functional outcomes induced by these two NKR-P1 receptors, shedding light on our understanding of how NK cell functions are regulated.
Notes: Adviser: J. C. Zuniga-Pflucker.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5059.