Diverse regulation of natural killer cell functions by dendritic cells
| dc.contributor.author | Mahmood, Sajid | |
| dc.contributor.examiningcommittee | Uzonna, Jude (Immunology) Soussi Gounni, Abdelilah (Immunology) Rempel, Julia (Immunology) Yao, Xiaojian (Medical Microbiology) Haeryfar, Mansour (University of Western Ontario) | en_US |
| dc.contributor.supervisor | Kung, Sam (Immunology) | en_US |
| dc.date.accessioned | 2014-09-04T15:17:51Z | |
| dc.date.available | 2014-09-04T15:17:51Z | |
| dc.date.issued | 2012 | en_US |
| dc.date.issued | 2014 | en_US |
| dc.degree.discipline | Immunology | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Natural killer (NK) cells are innate lymphocytes with inherent ability to eliminate infected cells and produce several cytokines/chemokines. They express surface receptors to sense environment and interact with other immune cells including the Dendritic cells (DC). Reciprocally, DCs are also shown to activate NK-cells. NK/DC cross-talk is well-documented, yet the molecular interactions and the diverse NK-cell activities regulated by DC remain unclear. Several target proteins such as MHC-1, Qa-1 mediate NK-cell target recognition. One such antigen, Ocil/Clr-b functions as a cognate ligand of NKR-P1B/D, NK-inhibitory receptor. In first aim of my study, I documented that deficiency of Ocil/Clr-b expression not only augmented the sensitivity of DC towards NK-cell cytotoxicity but also regulated the development of mature NK-cells. Thus suggesting NKR-P1B/D:Ocil to be another receptor:ligand system, besides Ly49:MHC-1, that regulates NK-cell responsiveness. Src homology region 2-containing protein tyrosine phosphatase-1 (SHP-1) transmits inhibitory signals of the specific NK-inhibitory receptors, including NKRP-1B/D. SHP-1 silenced NK-cells showed unaffected target recognition towards prototypic target cells in this study. In addition, these cells also displayed an unexpected phenotype of self-killing in-vitro, thus implicated SHP-1 as an important regulator of some other unappreciated NK-cell functions. The data from my third study suggest that DCs are directly implicated in the induction of NK-cell migration. In summary, using a novel live-cell imaging microfluidic platform and conventional transwell migration assay this project established a clear molecular link between DC-derived soluble factors such as IP-10 and NK cell-chemokine receptor such as CXCR3. Previously, GM-CSF was shown as an inflammatory cytokine, involved in the development of DC as well as in mediating Th-1 immune responses. In this study I found that GM-CSF regulates NK-cell migration negatively. Lastly, the fourth aim of my thesis highlighted the critical role of immature-DC in the induction of maturation receptors (NK1.1 & Ly49) on differentiating NK-cells. I successfully established a multi-stage in-vitro NK-cell differentiation model and found that differentiating NK-cells required an active engagement with DCs, in addition to the soluble factors. I believe my PhD project findings would impact the existing knowledge to harness DC-based NK cell therapies in clinical settings. | en_US |
| dc.description.note | October 2014 | en_US |
| dc.identifier.citation | Mahmood S, Kanwar N, Tran J, Zhang M-l, Kung SKP (2012) SHP-1 Phosphatase Is a Critical Regulator in Preventing Natural Killer Cell Self-Killing. PLoS ONE 7(8): e44244. doi:10.1371/journal.pone.0044244 | en_US |
| dc.identifier.citation | Mahmood, S., Nandagopal, S., Sow, I., Lin, F. and Kung, S. K. P. (2014), Microfluidic-based, live-cell analysis allows assessment of NK-cell migration in response to crosstalk with dendritic cells. Eur. J. Immunol.. doi: 10.1002/eji.201344244 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/23963 | |
| dc.language.iso | eng | en_US |
| dc.publisher | Public Library of Science | en_US |
| dc.publisher | Wiley Online Library | en_US |
| dc.rights | open access | en_US |
| dc.subject | Natural killer cell | en_US |
| dc.subject | Dendritic cell | en_US |
| dc.title | Diverse regulation of natural killer cell functions by dendritic cells | en_US |
| dc.type | doctoral thesis | en_US |