Lledó-Delgado Ana, Preston-Hurlburt Paula, Higdon Lauren, Hu Alex, James Eddie, Lim Noha, Long S Alice, McNamara James, Nguyen Hai, Serti Elisavet, Sumida Tomokazu S, Herold Kevan C
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Immune Tolerance Network, Bethesda, MD, 20814, USA.
Nat Commun. 2025 May 30;16(1):5033. doi: 10.1038/s41467-025-60276-5.
Teplizumab is approved for delaying the diagnosis of type 1 diabetes by modulating progression of disease. Compared to EBV-seronegative patients, those who are EBV-seropositive prior to treatment have a more robust response to teplizumab in two clinical trials. Here we compare the phenotypes, transcriptomes and development of peripheral blood cells before and after teplizumab treatment in participants. Higher number of regulatory T cells and partially exhausted CD8 T cells are found in EBV-seropositive individuals than in EBV-seronegative controls at the baseline in the TN10 and AbATE trials. Mechanistically, single cell transcriptomics and functional assays identify the downregulation of NFκB and T cell activation pathways after treatment in EBV-seropositive patients; among diabetes antigen-specific CD8 T cells, T cell receptor and mTOR signaling are also reduced. In parallel, signaling impairment is greater in adaptive than innate immune cells following teplizumab treatment in EBV-seropositive individuals. Our data thus indicate that EBV can impair signaling pathways in immune cells to modulate their responses in the context of type 1 diabetes.
替普珠单抗被批准用于通过调节疾病进展来延迟1型糖尿病的诊断。在两项临床试验中，与EB病毒血清学阴性患者相比，治疗前EB病毒血清学阳性的患者对替普珠单抗的反应更强。在此，我们比较了参与者接受替普珠单抗治疗前后外周血细胞的表型、转录组和发育情况。在TN10和AbATE试验的基线时，EB病毒血清学阳性个体中调节性T细胞和部分耗竭的CD8 T细胞数量高于EB病毒血清学阴性对照。从机制上讲，单细胞转录组学和功能分析确定了EB病毒血清学阳性患者治疗后NFκB和T细胞激活途径的下调；在糖尿病抗原特异性CD8 T细胞中，T细胞受体和mTOR信号也减少。同时，在EB病毒血清学阳性个体中，替普珠单抗治疗后适应性免疫细胞的信号损伤比先天性免疫细胞更大。因此，我们的数据表明，EB病毒可损害免疫细胞中的信号通路，从而在1型糖尿病的背景下调节其反应。
