Abstract
dc:description.abstractHedgehog (Hh) signalling is a classical morphogen pathway that regulates key processes in embryonic development, adult tissue homeostasis, and tumorigenesis. Recently, the Hh pathway has also been shown to be critical for CD8+ and CD4+ effector functions, acting in a cell-autonomous manner and downstream of the T-cell receptor. Whether this pathway is also functionally relevant in NK cells, an innate lymphocyte, has not been fully established. Moreover, the unique adaptations in how Hh signalling is orchestrated in lymphocytes are not well explored. Specifically, it is not known whether lymphocytes process and palmitoylate their Hh ligands or express Hh co-receptors, and whether these are essential for lymphocyte Hh signalling. In this thesis, I show that Hh signalling is induced downstream of bothNK activating receptor and cytokine receptor engagement. Using a conditional knock-out mouse model and pharmacological blockade, I find that the Hh pathway is critical for tumour cell killing in murine and human NK cells. Mechanistically, the Hh pathway impacts the kinetics of NK immune synapse formation, without affecting cytotoxic granule content and release or cytokine production. Importantly, I demonstrate that amplification of Hh signalling in human NK cells can enhance tumour cell killing. Next, I show that T cells can autocatalyse and palmitoylate their Hh ligands, similar to the classical Hh pathway; however, pharmacological inhibition of Hh palmitoylation did not impact Hh-driven T cell function. Finally, I found that lymphoid immune cells express only one Hh co-receptor, whereas myeloid immune cells express two, in contrast to classical Hh-responding cells with all three Hh co-receptors. Interestingly, by using specific co-receptor knock-out MEFs, I demonstrate that this co-receptor expression pattern likely explains theinability oflymphocytesto respond to exogenous Hh ligands. Taken together, this thesis establishes the role of Hh signalling in both murine and human NK cells and provides novel, therapeutically relevant insights into the adaptations of the Hh pathway in effector immune cells.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2025
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Afolaranmi, Oluwasegun
- Advisor dc:contributor.advisor
-
- de la Roche, maike
Subjects
dc:subject × 4Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.127260
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/398406