Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection

Abstract

Although the genetic basis and pathogenesis of type 1 diabetes have been studied extensively, how host responses to environmental factors might contribute to autoantibody development remains largely unknown. Here, we use longitudinal blood transcriptome sequencing data to characterize host responses in children within 12 months prior to the appearance of type 1 diabetes-linked islet autoantibodies, as well as matched control children. We report that children who present with insulin-specific autoantibodies first have distinct transcriptional profiles from those who develop GADA autoantibodies first. In particular, gene dosage-driven expression of GSTM1 is associated with GADA autoantibody positivity. Moreover, compared with controls, we observe increased monocyte and decreased B cell proportions 9-12 months prior to autoantibody positivity, especially in children who developed antibodies against insulin first. Lastly, we show that control children present transcriptional signatures consistent with robust immune responses to enterovirus infection, whereas children who later developed islet autoimmunity do not. These findings highlight distinct immune-related transcriptomic differences between case and control children prior to case progression to islet autoimmunity and uncover deficient antiviral response in children who later develop islet autoimmunity.

Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice

“…At early time points (i.e., 3 days after viral induction), flow cytometry revealed a decrease in mature NK cells in the blood of TYK2i-treated RIP-LCMV-GP mice, with a reciprocal increase in a subset of immature NK cells. This particular finding was notable given previous studies showing changes in NK cell phenotypes in established T1D (61) and the recent identification of an NK-enriched signature associated with both islet autoimmunity and T1D onset in the TEDDY and DIPP cohorts, which follow newborns with high genetic risk of T1D (62,63). In addition, we observed an increase in the percentage of CD11b+ DCs in the spleen of TYK2i-treated RIP-LCMV-GP mice, followed by a reduction of these cells in the PLN at day 7.…”

“…In contrast, in cancer models, PD1-expressing Tregs possess potent immunosuppressive effects and are associated with resistance to checkpoint inhibitors. In human cohort studies, the ratio between PD1 + effector and regulatory subsets has been proposed as a biomarker of cancer drug response (63), indicating there is complexity in interactions across different immune cell subsets that may not be appreciated when PD1 + is deleted in a single immune cell type.…”