Latent EBV impairs immune cell signaling and enhances the efficacy of anti-CD3 mAb in Type 1 Diabetes.
Teplizumab is approved for delay of diagnosis of type 1 diabetes and may modulate new onset disease. Compared to EBV seronegative patients, those who were EBV seropositive prior to treatment had a more robust response to drug in two clinical trials. We compared the phenotypes, transcriptomes, and development of peripheral blood cells before and after teplizumab treatment. Higher number of Tregs and partially exhausted CD8+ T cells were found in EBV seropositive individuals at the baseline in the TN10 and AbATE trials. Single cell transcriptomics and functional assays identified downregulation of NFkB and other pathways after treatment in treated EBV seropositive patients. Among diabetes antigen specific CD8+ T cells, T cell receptor and mTOR signaling were also reduced. Impairments in function of adaptive immune cells were enhanced by teplizumab treatment in EBV seropositive individuals. Our data indicate that EBV can impair signaling pathways in immune cells, that broadly redirect cell differentiation. Overall design: Islet autoantigen  and EBV tetramer positive CD8 cells were single cell sorted for scRNA-Seq analysis. Comparisions between placebo controls and teplizumab anti-CD3 treated patients were compared at baseline and 18 months with and without EBV seropositivity Please note that the indivisual sample information (for total 3668 samples) is provided in the 'sample_metadata.xlsx'.