Podocyte-derived exosomes instruct dendritic cell-dependent CD8+ T cell activation and proliferation in renal inflammation

• Podocyte exosomes activate T cells via MHC-I-dependent antigen cross-presentation. • Podocyte exosomes initiate local T RM activation; DCs drive systemic T cell expansion in MCD. • Rab27a-mediated exosome secretion is critical for PAN-induced kidney injury. • Inhibiting Rab27a/exosome release blocks T cell cascade and proteinuria in PAN-induced kidney injury. • Redefines podocytes as immunologically active via exosomal antigen presentation. Minimal Change Disease (MCD) represents a prevalent pathological cause of nephrotic syndrome. While podocyte injury is recognized as the direct cause of proteinuria in MCD, aberrant T-cell activation is a key driver of this podocyte damage. However, the absence of T-cell infiltration in renal biopsies and ineffectiveness of immunosuppressive therapy in a subset of patients suggest the existence of undiscovered key mechanisms underlying MCD immunopathogenesis. This study investigates the role of podocyte-derived exosomes (Pdo-Exos) in T cell activation via antigen presentation in MCD. Using an in vitro co-culture system, a puromycin aminonucleoside (PAN)-induced MCD mouse model, and clinical samples, we evaluated the immunostimulatory capacity of Pdo-Exos, focusing on antigen presentation via MHC-I and Rab27a-regulated exosome secretion. Pdo-Exos activated CD8 + T cells through MHC-I without promoting proliferation, indicating a role for dendritic cell-mediated cross-presentation. In OT-I mice, OVA-loaded Pdo-Exos exacerbated proteinuria and activated both tissue-resident and lymphoid T cells. MCD patients exhibited increased circulating activated T cells, and their podocyte exosomes showed significantly elevated MHC-I and co-stimulatory molecule CD80. Rab27a-dependent exosome secretion exacerbated disease severity, while inhibition of Rab27a mitigated proteinuria and inflammation. Podocyte-derived exosomes mediate CD8 + T cell activation by acting as antigen-presenting vesicles, with DCs facilitating T cell expansion. Rab27a-dependent exosome secretion contributes to MCD progression, highlighting a novel therapeutic strategy.