Single-cell transcriptomic analysis reveals T cell heterogeneity and metabolic reprogramming in human immune-mediated glomerulonephritis.

Immune-mediated glomerulonephritis (IMGN) is a major cause of kidney failure worldwide, yet the precise roles of T cells in its pathogenesis remain poorly understood. However, existing studies lack a comprehensive understanding of the characteristics and functional roles of IMGN T cells in the human context. Addressing this gap is crucial for advancing targeted therapies. By integrating single-cell RNA sequencing (sc-RNA-seq) data from three primary IMGN types-IgA nephropathy (IgAN), lupus nephritis (LN), and membranous nephropathy (MN)-we identified T cell subtype alterations at single-cell resolution. Utilizing advanced sc-RNA-seq computational pipelines, we constructed gene co-expression networks (GCNs), inferred T-cell differentiation trajectories, and assessed metabolic and intercellular signaling features. IMGN kidneys presented expanded T-cell compartments, with significant enrichment of cytotoxic natural killer T (NKT) cells and GZMK⁺ effector memory T (GZMK⁺ Tem) cells. Notably, LTB⁺ memory T cells (LTB⁺ Tm) were selectively elevated in IgAN and LN patients. A coexpression module centered on RGS1 was significantly correlated with 24-h proteinuria (p < 0.001). Metabolic profiling revealed subtype-specific disruptions in the glutathione (GSH) and 3-phospho-D-glyceroyl phosphate (3PD) pathways. Interaction analysis highlighted endothelial cells, mesangial cells, and fibroblasts as key mediators of pathogenic T-cell activation via defined ligand‒receptor pairs. This study provides the first comprehensive single-cell atlas of human IMGN T cells, revealing disease-specific T-cell states, metabolic signatures, and activation mechanisms. Our findings offer new insights into human renal immunopathology and identify promising therapeutic targets for IMGN.