Single Cell Mapping Identifies CD14+ Macrophages as Central Orchestrators of CD8+ T Cell Driven Immune Niches in clinical Type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by CD8+ T cell mediated destruction of pancreatic beta cells; however, the cellular interactions that organize immune activation within human islets remain poorly understood. Here, we integrated thirteen CD45+ immune cell single cell RNA sequencing datasets from human islets spanning non-diabetic donors, stage 3 T1D, and type 2 diabetes (T2D) to comprehensively define immune cell heterogeneity and decipher the intercellular communication networks that drive islet autoimmunity. We identified distinct macrophage states, including CD14+ inflammatory macrophages, CD14+/TREM2+ macrophages, and quiescent-like macrophages, together with CD8+ T cells and mast cells. Trajectory and communication analyses revealed CD14+ macrophages as central immune hubs that coordinate antigen presentation, costimulatory signaling, and inflammatory chemokine production. Compared with non diabetic and type 2 diabetic islets, T1D macrophages displayed a disease-specific inflammatory program characterized by enhanced TNF, IL18, CCL3, CCL4, CCL5, and ICOSLG expression, supporting CD8+ T cell recruitment and activation. Spatial transcriptomic analysis of human T1D pancreas further demonstrated a beta cell macrophage CD8+ T cell inflammatory niche, where macrophage-derived CCL3/CCL4/CCL5 and CD8+ T cell-expressed CCR5 suggest a chemokine-mediated mechanism of immune targeting. Together, these findings identify CD14+ macrophages as key orchestrators of a feed-forward inflammatory circuit driving human islet autoimmunity.