Diverse regulation of natural killer cell functions by dendritic cells
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Date
2012, 2014
Authors
Mahmood, Sajid
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
Wiley Online Library
Wiley Online Library
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.
Description
Keywords
Natural killer cell, Dendritic cell
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
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
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