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T cell responses are crucial in viral clearance, but little is known of the role of cytotoxic CD4+ T cells in the control of viral infection. Chronic hepatitis B virus (HBV) infection is a global public health problem. In the first part of my study, HBx-specific T cell responses were investigated in patients with chronic HBV infection and their functional profiles were evaluated in vitro. Stronger HBx-specific T cell responses were associated with HBeAg clearance and lower HBsAg levels. X146-154-specific CD8+ T cells can produce effector cytokines and express CD107a when encountering HBV-infected HepG2hNTCP cells. Furthermore, they can kill HBV-infected cells and suppress HBV replication and antigen production. Among HBx-specific CD4+ T cells, X89-103-CD4+ T cells showed the greatest cytotoxicity, while X105-119-CD4+ T cells did not exhibit any killing capacity. Interestingly, highly cytotoxic HBx-specific CD4+ T cells displayed high functional avidity and degranulation, and can inhibit HBV replication in vitro. These data demonstrate the potent role of HBx-specific T cells in controlling HBV infection and highlight their potential for future interventions. In March 2020, COVID-19 pandemic started in UK, my project expanded to study the role of T cell responses, in particular potential escape variants in circulating virus and cytotoxic CD4+ T cells in SARS-CoV-2 infection. Robust SARS-CoV-2 specific memory T cell responses were observed in convalescent COVID-19 individuals. Three dominant spike CD4+ T cell epitopes, one ORF3a and three nucleocapsid CD8+ epitopes were identified in this study. We first showed that several mutations within nucleocapsid and ORF3a CD8+ epitopes resulted in loss of T cell responses assessed by IFN-γ ELISpot assays and cytotoxic killing assays. This demonstrates the potential for T cell evasion and highlights the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity. We then characterised T cell responses to the three dominant spike CD4+ T cell epitopes and evaluated their antiviral activity, including cytotoxicity and antiviral cytokine production. We found that S866-880-specific CD4+ T cells exhibited highest cytotoxicity and correlated with strongest antiviral efficacy, while S166-180-specific CD4+ T cells showed lowest cytotoxicity. Our single cell T cell receptor (TCR) analysis revealed diverse TCR usage including unexpected high level of public TCR usage among all three epitope specific T cells. Surprisingly, CD4+ cytotoxic T lymphocytes (CTLs) were found to have signalling and cytotoxic pathways distinct from classical CD8+ CTLs, with increased expression of chemokines and tissue homing receptors promoting migration. In addition, our longitudinal study showed that robust immune memory 6-9 months post-infection or vaccination provides CD4+ T cells with potent antiviral activity. In summary, our study in chronic HBV infection and SARS-CoV-2 infection revealed the unique features of CD4+ CTLs that use distinct functional pathways to non-cytotoxic CD4+ T cells and highlighted that induction of potent memory CD4+ CTLs could be a potential approach for future vaccine designs by supporting early viral control.


Thesis / Dissertation

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SARS-CoV-2, HBV, T cells