Inflammatory dendritic cell drives intra-renal T cells to double-negative T cells in lupus nephritis 4065

Description Lupus nephritis (LN) is a severe kidney complication of SLE, yet the immunological mechanisms driving intrarenal inflammation are poorly understood. Our studies identified FCER1G as the most upregulated transcript in the glomeruli of human LN, correlating with disease pathogenesis and proteinuria. We found that inflammatory dendritic cells (infDC), characterized by unique marker combinations, are a major cell type expressing FCER1G. These cells accumulate in the peri-glomerular (PG) space and are found near CD3+ T cells in LN kidney. ChipCytometry quantification further revealed the PG as a key immune region, with CD3+CD4-CD8- double-negative T cells (DNT) being the major T cell subtype in the PG. FACS analysis of the proteinuric NZM 2410 (prot-NZM) mouse model identified upregulation of DNT cells, but not Th1, Th17, CD4, or CD8 cells, compared to pre-proteinuric NZM mice. In a humanized lupus (Hu-lupus) mouse model, we observed significantly higher levels of infDC subtypes and DNT cells compared to Hu-healthy mice. Most CD3+ cells in Hu-lupus mice were TCRαβ+TCRγδ-CD4-CD8-PD1+, indicating a self-reactive, pro-inflammatory DNT cell subset. Co-culture experiments confirmed that Fc?RI+ infDC from prot-NZM kidneys induced DNT cell polarization and increased pro-inflammatory cytokine secretion, including TNF-α, IL-1β, and CXCL1. These data suggest that infDC plays a central role in driving kidney inflammation and LN pathogenesis.