CD4+ T cells in Type 1 Diabetes: Inferring Stage-specific Dysregulation from scRNA-seq

Deciphering the cellular and molecular mechanisms of type 1 diabetes (T1D) has long been a central goal in immunology. Here, we perform a large-scale single-cell transcriptomic analysis of peripheral blood mononuclear cells from children with T1D, their first-degree relatives, and healthy controls, enabling high-resolution profiling of immune dynamics across disease stages. We identify distinct immune signatures associated with pathogenesis: an expansion of non-mature regulatory T cells (Tregs) marks new-onset T1D, coinciding with clinical manifestation. During active autoimmunity, we observe increased Th22 cells linked to tumor necrosis factor (TNF) and interleukin (IL)-6 upregulation, reduced mucosal-associated invariant T (MAIT) cells with altered functional activity, and elevated ADAM10 and ADAM17 expression, promoting proinflammatory intercellular signaling. In contrast, the later phase of disease is characterized by Th17 cell accumulation and enhanced signalling through TGF-β1 and IL-12. Transcriptional regulatory network analysis highlights BACH2 as a key regulator of Treg maturation, implicating its dysregulation in immune tolerance breakdown. Dynamic shifts in CD4+ T cell subsets and cell-cell communication reveal stage-specific immunological trajectories. These findings provide a comprehensive map of systemic immune remodelling in T1D and uncover potential biomarkers and therapeutic targets for stage-stratified intervention.