Thesis Jet van den Dijssel

abstract

CD8⁺ T cells are essential for antiviral immunity, reducing disease severity by recognizing and targeting a broad range of virus-derived epitopes. This thesis identified highly conserved SARS-CoV-2-specific CD8⁺ T cell epitopes to study the role of CD8⁺ T cells in healthy and immunocompromised individuals. SARS-CoV-2 infection induced robust virus-specific CD8⁺ T cell responses exhibiting a central memory phenotype, independent of age and/or latent cytomegalovirus. Although the immunodominant SARS-CoV-2-specific CD8⁺ T cell epitopes were mostly derived from non-spike proteins post-infection, spike-specific responses were boosted after mRNA vaccination while non-spike responses remained stable. In a cohort of autoimmune disease patients, including inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis patients (RA), we assessed the impact of immunosuppressive therapies on vaccine-induced immunity. Anti-CD20-treated MS patients showed impaired humoral responses, which correlated with the serum concentrations of anti-CD20, but preserved CD8⁺ T cell responses. Methotrexate-treated RA patients exhibited diminished T cell activation, suggesting delayed or compromised immunity. TNF inhibitor-treated IBD patients mounted strong spike-specific central memory CD8⁺ T cell responses, comparable to those in untreated and healthy controls. To prepare for emerging viruses, designing vaccines that induce broad and long-lasting immune responses, while optimizing vaccination timing with immunosuppressive therapies, may enhance immunity in healthy and immunocompromised individuals. Additionally, novel techniques characterizing the functionality of epitope-specific CD8⁺ T cells are valuable to understand which epitopes are important for optimal immunity. Overall, this thesis expands our understanding of SARS-CoV-2-specific CD8⁺ T cells, underscoring the importance of their conserved immunity in healthy and vulnerable populations.