Investigating factors affecting functionality of virus-specific CD8+ T cells

Thesis

CD8+ T cells play a fundamental role in protection against viral infections, including SARS-CoV-2 and influenza. Although CD8+ T cells are well studied, many questions regarding their function remain. As T cells play a key role in determining disease outcome during respiratory viral infection, understanding the factors that influence their function is of paramount importance. Focussing on the T cell response to influenza and SARSCoV-2, we address two key research questions in this thesis: how does antigenspecificity shape the ageing trajectory of CD8+ T cells, and which features of CD8+ T cells contribute to their association with severe disease.

The first part of this study (Chapter 3) addresses the question of how antigen specificity shapes the ageing trajectory of CD8+ T cells, focussing on the immunodominant influenza M158-66-specific T cell response. We perform single-cell RNA sequencing of longitudinal samples from three individuals over a 19-year period to determine how M158- 66-specific T cells change with age and how these changes compare to those in the broader CD8+ T cell population. We observed reduced diversity of the M158-66-specific TCR repertoire as the donors aged and identified transcriptomic changes, including altered expression of genes associated with metabolism and cytotoxicity. Several of the transcriptomic changes are unique to M158-66-specific T cells, highlighting that T cells with different specificities undergo distinct age-related changes.

Although CD8+ T cells protect against viral infections, they can also be associated with driving immunopathology but the factors that cause them to do this are not well understood. In Chapter 4 we focus on the SARS-CoV-2 ORF3a207-215-specific T cell response which has been associated with severe disease in COVID-19. We identify pairs of ORF3a207-215-specific T cell clones with identical TCR sequences but differences in their functionality and use the highly functional clones as an example of T cells that can contribute to immunopathology. Through omic analysis we identify high expression of integrins on the highly functional T cells and thus explore how integrin molecules influence T cell function.

In Chapter 5, we utilise in vitro functional assays and immune synapse imaging to investigate how the integrins a4b1 and a4b7 influence T cell function and whether the expression of these integrins could be related to the association of ORF3a207-215-specific T cells with disease severity. We found that the integrins a4b1 and a4b7 increased T cells function, and immune synapse imaging revealed localisation of a4, b7 and b1 in the immune synapse. Thus, these integrins may function as fine tuners of T cell activity and enhance T cell functionality through stabilisation of the immune synapse. 

Authors: Pidoux, M

• DOI: 10.5287/ora-bpzdd85bx
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Immunology