Abstract
Abstract Teplizumab, a FcR non-binding anti-CD3 mAb, is approved to delay progression of type 1 diabetes (T1D) at-risk patients. Previous investigations described the immediate effects of the 14-day treatment, but longer-term effects of the drug remain unknown. We analyzed the phenotypes, transcriptome, and repertoire of peripheral blood and autoreactive CD8+ T cells from individuals at-risk for T1D, before and after teplizumab. There were changes in CD4+ and CD8+ T cells at 3 months and 18 months after treatment in genes related to immune regulation. The differential gene expression in the T cells increased after drug was cleared. Persistent EOMES expression was a predictor for the time to clinical T1D diagnosis. Our trajectory analysis showed differentiation into cells with gene signatures related to immunoregulation and exhaustion after teplizumab treatment. This analysis aligned with inhibition of expansion of autoreactive CD8+, which was observed with the placebo, but not following teplizumab. These findings illustrate that a single course of teplizumab can instigate substantial T cell changes at 3 months, with evolution of CD8+ T cell exhaustion up to 18 months. Teplizumab restrains the expansion of autoantigen reactive CD8+ cells, suggesting mechanisms underlying operational tolerance.
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