Molecular Mechanisms and Functional Role of Hepatic Invariant Natural Killer T cell Recruitment Following Sterile Injury in the Liver
| atmire.migration.oldid | 5552 | |
| dc.contributor.advisor | Kubes, Paul | |
| dc.contributor.author | Liew, Pei | |
| dc.contributor.committeemember | Mody, Christopher | |
| dc.contributor.committeemember | Eksteen, Bertus | |
| dc.contributor.committeemember | Mallevaey, Thierry | |
| dc.contributor.committeemember | Senger, Donna | |
| dc.date.accessioned | 2017-05-02T14:40:31Z | |
| dc.date.available | 2017-05-02T14:40:31Z | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017 | en |
| dc.description.abstract | After traumatic injury, the body must return to homeostasis as quickly as possible through initial destruction of injured cells and clearance of debris (inflammation) followed by a critical switch towards vascular and tissue reconstruction (non-inflammatory restitution). While many different immune cells are known to infiltrate a site of injury for specific effector functions, it is reasonable to hypothesize that some cells function as directors of inflammation whereupon sensing the degree of injury, these cells orchestrate the local immune response towards a restitution phase by affecting the local cytokine milieu. This progression could be defective in non-resolving sterile injuries where a failure to transition to repair or a persistence of inflammation leads to chronic inflammation. Invariant Natural Killer T (iNKT) cells are innate lymphocytes that prominently regulate inflammation due to their rapid release of pivotal cytokines during pathological states, which can then differentially impact the downstream immune response and disease outcome. In this thesis, using intravital microscopy, we observed that patrolling iNKT cells in the liver were initially selectively repelled from a site of hepatic injury but were subsequently strategically arrested via self-antigens and cytokines, circumscribing the injured site at exactly the location where monocytes co-localized and hepatocytes proliferated. iNKT cell activation signals were temporally- and spatially-regulated as self-antigen presentation via CD1d occurred first before being closely followed by cytokine signaling. Additionally, both activation signals were located adjacent to the injury and not further away. Activation of iNKT cells through these two mechanisms resulted in the production of IL-4 but not IFN-γ which promoted increased hepatocyte proliferation, monocyte transition (from classical to tissue repair monocytes) and improved healing. Disruption of any of these mechanisms led to a delay of wound healing. We show that self-antigens, beyond the known role in iNKT cell development, were fundamental for monocyte transition, appropriate collagen deposition and hepatocyte proliferation. Hepatic iNKT cells were instrumental in directing and modulating the transformation from inflammation to tissue restitution after sterile injury in the liver for essential timely wound repair. | en_US |
| dc.identifier.citation | Liew, P. (2017). Molecular Mechanisms and Functional Role of Hepatic Invariant Natural Killer T cell Recruitment Following Sterile Injury in the Liver (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26990 | en_US |
| dc.identifier.doi | http://dx.doi.org/10.11575/PRISM/26990 | |
| dc.identifier.uri | http://hdl.handle.net/11023/3805 | |
| dc.language.iso | eng | |
| dc.publisher.faculty | Graduate Studies | |
| dc.publisher.institution | University of Calgary | en |
| dc.publisher.place | Calgary | en |
| dc.rights | University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. | |
| dc.subject | Immunology | |
| dc.subject.other | Intravital Imaging | |
| dc.subject.other | Invariant Natural Killer T cells | |
| dc.subject.other | Sterile Inflammation | |
| dc.subject.other | wound healing | |
| dc.subject.other | Liver | |
| dc.subject.other | Monocytes | |
| dc.subject.other | Cell death | |
| dc.subject.other | Self-antigens | |
| dc.subject.other | Collagen deposition | |
| dc.title | Molecular Mechanisms and Functional Role of Hepatic Invariant Natural Killer T cell Recruitment Following Sterile Injury in the Liver | |
| dc.type | doctoral thesis | |
| thesis.degree.discipline | Immunology | |
| thesis.degree.grantor | University of Calgary | |
| thesis.degree.name | Doctor of Philosophy (PhD) | |
| ucalgary.item.requestcopy | true |