Antigen-specific B and T cell responses in immunosuppressed patients Lessons learnt during the era of SARS-CoV-2 vaccination

During the SARS-CoV-2 pandemic, understanding protective immunity after infection or vaccination became a national and scientific priority. While most research has focused on antibody (humoral) responses, T cells also play a crucial role, especially when antibody production is impaired. This thesis investigates how immunosuppressive therapies in patients with autoimmune diseases affect the induction of antigen-specific T and B cell responses after SARS-CoV-2 mRNA vaccination. First, we optimized the enzyme-linked immunosorbent spot (ELISpot) and activation-induced marker (AIM) assays to improve the detection of SARS-CoV-2-specific T cells. Next, we used high-dimensional flow cytometry followed by unsupervised clustering to characterize the complexity of SARS-CoV-2-specific B cell differentiation over time. In multiple sclerosis, patients are often treated with B cell depleting therapies, such as ocrelizumab or fingolimod. Ocrelizumab-treated patients retained SARS-CoV-2-specific T cell responses, whereas fingolimod-treated patients showed impaired cellular immunity. In RA patients, methotrexate reduced CD4 T cell induction which could explain the slightly slower humoral responses. Conversely, TNF inhibitor-treated IBD patients showed impaired spike-specific B cell responses, particularly affecting germinal center-derived (CD11c−) populations, while extrafollicular-like CD11c+ B cells remained unaffected—suggesting TNF signaling is crucial for germinal center formation. Lastly, SARS-CoV-2 vaccination triggered non-cognate (‘bystander’) B cell activation, with transient increases in unrelated antibody titers. Possibly, the antigen-independent reactivation of memory B cells could help maintain circulating antibody levels, thereby protecting against future infections. Together, this work advances our understanding of adaptive immunity under immunosuppressive conditions and informs vaccine strategies for vulnerable patient populations.