Single-cell dissection of CD8+ T cell-driven immune dysregulation in type 1 diabetes mellitus: Mechanistic links to diabetic foot pathogenesis.

BACKGROUND

Type 1 diabetes (T1DM) is characterized by autoimmune destruction of pancreatic β-cells and systemic immune dysregulation, yet the cellular networks driving disease progression and their potential link to diabetic complications remain unclear.

METHODS

We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from 46 stage 3 T1DM patients and 31 matched controls, integrating transcriptomic, cellular interaction, and functional enrichment analyses.

RESULTS

Unsupervised clustering of 87,542 cells revealed profound immune dysregulation in T1DM, including cytotoxic CD8+ T cell expansion (70 % increase) and Treg depletion (>50 % reduction). CD8+ T cells exhibited hyperactivation of cytotoxic effectors (GNLY, GZMB) and inflammatory mediators (IL32, S100A4), alongside suppressed regulatory genes (FOXP3, IL2RA). Cell-cell communication analysis identified amplified GALECTIN-CD44 signaling between monocytes/DCs and CD8+ T/NK cells, driving proinflammatory crosstalk. Strikingly, a novel exhausted CD4+ subset (PDCD1+, LAG3+) emerged exclusively in T1DM.

CONCLUSION

Our findings establish CD8+ T cells as central orchestrators of T1DM pathogenesis through synergistic cytotoxic hyperactivity and regulatory collapse. The identified GALECTIN-CD44 axis and JAK-STAT/TGF-β imbalances may extend beyond pancreatic autoimmunity, providing mechanistic insights into systemic complications (e.g., impaired wound healing and chronic inflammation) observed in diabetic patients. These dysregulated networks offer novel therapeutic targets for restoring immune homeostasis in T1DM and its associated comorbidities.