Antigen regulation of t cell receptor signalling and immune checkpoint expression in health and disease

Thawait, Natasha ORCID: 0000-0002-8321-3292 (2021). Antigen regulation of t cell receptor signalling and immune checkpoint expression in health and disease. University of Birmingham. M.Sc.

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Abstract

Binding of cognate antigen to the T cell receptor (TCR) results in downstream signalling, which controls T cell activation and effector function. It is still however controversial how antigen dose and affinity, as well as over-expression of immune checkpoints in the tumour microenvironment (TME) affect such processes. The novel Nr4a3-Timer of cell kinetics and activity (Tocky) system was used for the temporal analysis of CD8+ T cell activation through distal TCR signalling analyses. It was first found that expression of two downstream TCR genes respond differently to signalling; Nr4a1 requires shorter, weaker signals than Nr4a3. Using the OTI TCR transgenic system and modified peptides, it was established that TCR affinity affects the antigen dose required to trigger expression of IFNγ and PD-1 as well as affecting maximum response, by altering TCR signalling dynamics. Finally, the in vivo effects of the TME on T cell activation, immune checkpoints and IFNγ expression was investigated, resulting in a set of findings that provide an overview of T cell activation and checkpoint expression in response to tumour antigens. This project therefore broadens our understanding of how antigen regulates CD8+ T cell biology and proposes future lines of investigation to understand anti-tumour T cell responses.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):