Abstract Text: Teplizumab has been approved for delay of Type 1 diabetes (T1D) in individuals at-risk. We aimed to study factors that affect responses to treatment. Latent DNA viruses may affect adaptive immune responses. In two T1D trials (for prevention (TN10) and treatment (AbATE)), EBVsero+ individuals had a more robust clinical response to teplizumab: in TN10, in EBVsero+ a delay in diagnosis of T1D of 52.8 (p=0.01) vs 28.7 mos (p=0.08) in EBVsero- with a 42.3 mo difference in sero+ vs- among teplizumab treated participants (p=0.08). We found an increased frequency of CD8+ T cells expressing TIGIT and KLRG1 (“partially exhausted”) in the EBV sero+ in the two trials by flow cytometry(p < 0.0001 in both). To identify the effects of EBV, we performed scRNAseq on peripheral blood in the prevention study. In EBVsero+ at enrollment, there was a greater number of CD8+ effector and effector memory cells after teplizumab in EBV+ at approximately 3 mos and 18 mos (p=0.03 and 0.06). Importantly, teplizumab led to reduced expression of genes associated with cell signaling (NFkB, z=-4.12 p< 0.01, mTOR, z=-3.3 p= 0.003) that was maintained to 18 mos (NFkB, z=-3.9, p< 0.01, mTOR, z=-3.1 p= 0.002) in the EBVsero+ vs - participants. Moreover, in B cells we found reduced B cell receptor signaling (z=-4.3, p< 0.01). These results suggest that teplizumab treatment in patients with prior infection with EBV expands effector and effector memory CD8+ T cells with impaired signaling. There are also effects on B cells that may enhance the therapeutic responses.
