Tu203 - Epstein-Barr Virus Seropositivity Modulates the Immune Response to T Cell-Targeted Therapies in Type 1 Diabetes.

Abstract Text: Teplizumab, an anti-CD3 monoclonal antibody, is approved for delaying type 1 diabetes (T1D) onset and modulating new-onset disease. Epstein-Barr virus (EBV) has been linked to autoimmune diseases, and our findings suggest that EBV serostatus influences the immune response to teplizumab and other biologic therapies. In the TN10 and AbATE trials, EBV-seropositive individuals experienced a more pronounced delay in T1D diagnosis and exhibited a greater C-peptide response compared to EBV-seronegative individuals. A similar trend was observed with anti-thymocyte globulin (ATG), which improved C-peptide responses in EBV-seropositive individuals, suggesting a broader immunomodulatory effect. At baseline in the TN10 trial, EBV-seropositive individuals had higher numbers of regulatory T cells (Tregs) and "partially exhausted" CD8+ T cells. Post-treatment, single-cell transcriptomics and functional assays revealed downregulation of NF-κB, T cell receptor, and mTOR signaling pathways, with greater impairment in adaptive immune cells, including B cells. Additionally, EBV-seropositive individuals displayed lower levels of anti-drug antibodies (ADA) in the AbATE. There was an increased expression of immune markers such as EOMES or KLRG1+ and TIGIT+ after teplizumab in the CD8 T cells. EBV-reactive T cells expanded following teplizumab, while T1D-specific T cells were curtailed. These findings suggest that EBV infection may alter immune signaling pathways, modulating T cell differentiation and enhancing the therapeutic response to teplizumab and ATG.