Public Defence: Hanna Chan

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Trial Lecture – time and place

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Adjudication committee

• First opponent: Professor Ondrej Stepanek, Czech Academy of Sciences, Czech Republic
• Second opponent: Professor Carolyn King, University of Basel, Switzerland
• Third member and chair of the evaluation committee: Professor Jason Matthews, Faculty of Medicine, University of Oslo

Chair of the Defence

Professor emeritus Inger Sandlie, University of Oslo

Principal Supervisor

Professor Anne Spurkland, University of Oslo

Summary

T cells play a crucial role in the immune system to combat infections and have been exploited for use in immunotherapies. Intracellular signalling networks ensure that T cells respond in an appropriate and sufficient manner. Characterising the mechanisms of how T cell intracellular signalling pathways are regulated is imperative in understanding T cell function.

In this work, we focused on an adaptor protein implicated in T cell intracellular signalling, T cell specific adaptor protein (TSAd), whose functional role remains elusive. TSAd contains several regions for protein interaction, including the Src homology 2 domain (SH2). Given the importance of SH2 domains in phosphotyrosine (pTyr) signalling, the aim of this work was to further characterise TSAd SH2 interactions and its functional role in T cells.

Firstly, we established a work-flow to introduce point mutations in Jurkat T cells by using CRISPR/Cas9 gene editing. Using this work-flow, we attempted to render the TSAd-SH2 domain non-functional by mutating its conserved arginine. Secondly, we characterised the interactome of the TSAd SH2 domain in an unbiased manner. Using affinity-purification mass spectrometry and biochemical methods, we identified two novel ligands of TSAd, namely DOK2 and PTPN11. The sites of interaction were determined and binding was dependent on a functional TSAd SH2 domain. Lastly, the functional role of TSAd in T cells was addressed using TSAd deficient T cells. We confirmed some previously reported phenotypes as well as addressed discrepancies of the data in the field in light of the novel interactome data. Overall, our findings provide further insight into which signalling pathway(s) that TSAd may be implicated in. This insight may aid in future development of immunotherapies as well as elucidating mechanisms of T cell driven pathologies.

Additional information

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