University of Cambridge
T cell receptor- and calcium-induced Gli signalling in CD8+ T cell effector function
Abstract
dc:description.abstractCD8+ cytotoxic T lymphocytes (CTLs) are potent effector cells of the immune system, capable of directly lysing neoplastic and infected cells. The Hedgehog (Hh) signalling pathway - a critical regulator of embryonic development and adult tissue maintenance - is induced in CTLs following TCR stimulation and has been shown to be important in CTL cytotoxic ability through its role in the formation of the immune synapse. Recently, data from our laboratory demonstrated that Gli1, an important downstream Hh transcription factor, is important for the cytotoxic ability of murine CTLs in vitro and revealed that L-type voltage-gated Ca2+ channels (Cav1) are crucial for Gli1 induction. However, the role of Gli1 in the context of cytotoxic CTL function in vivo has not been explored. Furthermore, expression and functional relevance of GLI transcription factors in human CTLs is unknown as is the therapeutic potential of the Cav1/Ca2+ influx-Gli1 axis to enhance killing capacity in CTLs. In this thesis I demonstrate that Gli1 is a potent modulator of CTL cytotoxicity in vivo and has great influence on human CTL function. Furthermore, I show that Cav1 channel-mediated Ca2+ flux leading to Gli1 induction is necessary for cytotoxic ability in vitro and in vivo. I utilise a small molecule Cav1 agonist and overexpression of a Cav1.4 gain-of-function mutation to augment Cav1-mediated Gli1 induction in CTLs. Importantly, the novel Cav1-Gli1 axis can be used to enhance not only murine and human CTL capacity but also other cytotoxic lymphocytes including murine cytotoxic CD4+ T cells and human Vγ9Vδ2+ and Vδ1+ T cells without affecting survival and differentiation in vitro. Taken together, this thesis establishes the functional importance of Gli1 and Cav1 channel-mediated Ca2+ flux for CTL effector function and may guide future therapeutic approaches against infection and cancer.
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
-
- Beke, Flavio
- Advisor dc:contributor.advisor
-
- de la Roche, Maike
Subjects
dc:subject × 8Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.122768
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/391756