TGF-β-mediated crosstalk between TIGIT Tregs and CD226CD8 T cells in the progression and remission of type 1 diabetes.

Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGITCCR7 Tregs and CD226CCR7CD8 cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGITCCR7 Tregs and CD226CD8 T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGITCCR7 Tregs may inhibit CD226CCR7CD8 T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D.