Natural killer (NK) cell deficiency (NKD) occurs when an individual’s major clinical immunodeficiency derives from abnormal NK cells and is associated with several genetic etiologies. Three categories of β actin-related diseases with over 60 ACTB variants have previously been identified, none with a distinct NK cell phenotype. An individual with mild developmental delay, macrothrombocytopenia, susceptibility to infections, molluscum, and EBV-associated lymphoma had functional NK cell deficiency for over a decade.
A de novo ACTB variant encoding G342D β actin was identified and was consistent with the individual’s developmental and platelet phenotype. This novel variant also was found to have a direct impact in NK cells, as its expression in YTS (YTS-NKD) cells caused increased cell spreading in lytic immune synapses created on activating surfaces. YTS-NKD cells were able to degranulate and perform cytotoxicity, but demonstrated defective serial killing owing to prolonged conjugation to the killed target cell and thus were effectively unable to terminate lytic synapses. G342D β actin results in a novel mechanism of functional NKD via increased synaptic spreading and defective lytic synapse termination with resulting impaired serial killing leading to overall reductions in NK cell cytotoxicity.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/sa30-en84 |
| Date | January 2024 |
| Creators | Reed, Abigail Elizabeth |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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