IFI27 modulates the immune response in childhood neuropsychiatric systemic lupus erythematosus by regulating CD8+ T cell function via the IFN-I signaling pathway.

BACKGROUND

Childhood neuropsychiatric systemic lupus erythematosus (cNPSLE) represents one of the most severe complications of systemic lupus erythematosus. Aberrant CD8+ T cell activation and hyperactivated IFN-I signaling contribute to cNPSLE immunopathogenesis. IFI27, a key IFN-I-stimulated gene, has not been functionally characterized in cNPSLE.

METHODS

The scRNA-seq data from cNPSLE patients were analyzed to characterize immune cell heterogeneity and interactions using cell clustering, differential gene screening, GO enrichment, and CellChat analysis. NPSLE mouse models were established to evaluate cognitive function, disease activities, and neuropathological changes. IFN-I pathway activation, IFI27 expression, and CD8+ T cell quantity and activation were assessed using WB, qRT-PCR, and flow cytometry, respectively. The co-culture of CD8+ T cells with BV2 microglia was established to elucidate the regulatory effect of CD8+ T cell-derived IFN-I signaling on microglial function via morphological observation, ELISA, and Transwell assays.

RESULTS

Increased proportions of IFI27+CD8+ T cells were observed in the peripheral blood of cNPSLE patients. This subset highly expressed IFI27 and was markedly enriched for the IFN-I pathway, potentially promoting neuroinflammation. Animal experiments confirmed that IFI27 silencing ameliorated cognitive impairment, reduced autoantibody levels, and suppressed IFN-I pathway activation and effector subset differentiation in CD8+ T cells in NPSLE mice. These protective effects were reversed by IFN-I agonist treatment. Mechanistically, IFI27 activated the IFN-I pathway in CD8+ T cells, promoting microglial activation, phagocytic function, and pro-inflammatory cytokine release.

CONCLUSION

IFI27 accelerates cNPSLE progression by stimulating the IFN-I pathway in CD8+ T cells, driving their differentiation into cytotoxic phenotypes, and enhancing microglial activation and neuroinflammation.