A License to Kill: Understanding Natural Killer Cell Licensing to Fight Cancer

<p>Natural killer (NK) cell education is an essential developmental process for NK cell effector function, that renders some NK cells “licensed” and others “unlicensed” (with heightened or lowered effector function potential, respectively) against tumor and targets lacking self-molecules. However, the underlying mechanisms responsible for the heightened effector responses of licensed cells remain unknown. Using NK cells derived from humans and expanded <em>ex vivo </em>we performed high-throughput protein expression analysis, and identified multiple proteins that are differentially regulated in licensed and unlicensed human NK cells before and after inhibition by killer-cell immunoglobulin-like receptors (KIRs) and activation by the NKp46 natural cytotoxicity receptor, including several related to cellular metabolic pathways. We explored cellular metabolism in the two subsets and found that licensed NK cells are highly glycolytic, and use glycolysis and mitochondrial respiration for cytolysis of leukemia targets, whereas unlicensed NK cells are dependent on mitochondrial respiration. We determined the metabolic pathways that are necessary for licensed and unlicensed NK cells to elicit a cytolytic response using metabolic inhibitors to inhibit glycolysis or mitochondrial respiration metabolic pathways in the NK cells during a cytotoxicity assay. We observed that licensed NK cells utilize both glycolysis and mitochondrial respiration to perform cytolysis whereas unlicensed NK cells only use mitochondrial respiration for their cytolytic response against leukemia targets. To our knowledge, this is the first description of the underlying mechanisms that explain the cytolytic differences between licensed and unlicensed NK cells. Our findings provide a groundbreaking platform to further explore and manipulate metabolism in licensed and unlicensed NK cells to improve NK cell immunotherapy.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2017

Authors dc:creator

• Schafer, Jolie
• <p><a href="http://orcid.org/0000-0002-5770-2973" target="_blank">0000-0002-5770-2973</a></p>

Contributors dc:contributor

• Shulin Li
• Dean Lee
• Michael Curran

• Natural Killer Cells
• KIR
• immunology
• immunometabolism
• metabolism
• education
• licensing
• Immunology and Infectious Disease
• Medicine and Health Sciences
• Other Immunology and Infectious Disease

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/812

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1855