CD8 T lymphocytes infiltrate the kidneys and correlate with disease progression in B6. NZMSle1/Sle2/Sle3 lupus mice

Abstract Background Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) characterized by immune-mediated renal damage. While intrarenal CD8 + T cell infiltration has been linked to disease activity in patients, their pathogenic contribution remains unclear, partly due to the lack of mechanistic insight from murine models. Methods We investigated renal CD8 + T cell infiltration in female B6.NZMSle1/Sle2/Sle3 lupus-prone mice across different ages, comparing them to C57BL/6 controls. Histopathology was assessed using human-derived NIH Activity and Chronicity Indices, complemented by fibrosis quantification, immunohistochemistry, and digital image analysis. Kidney T cell subsets were evaluated by flow cytometry, and transcriptomic profiling was performed using microarrays. Results Lupus-prone mice developed progressive kidney injury resembling human LN, with increasing NIH activity scores, collagen deposition, however with interindividual heterogeneity. CD8 + T cell infiltrates were significantly elevated in lupus kidneys as early as 3 months, rising with age and correlating with histological activity. CD8 + T cells localized to periglomerular and peritubular regions but did not predominate over CD4 + T cells, as confirmed by flow cytometry. Transcriptomic analyses revealed age-dependent upregulation of interferon (IFN)-stimulated genes, B cell–associated transcripts, and extracellular matrix remodeling pathways, while T cell– related signatures were more variable. Conclusions B6.NZMSle1/Sle2/Sle3 mice recapitulate several histopathological and molecular features of human LN, including progressive fibrosis and intrarenal CD8 + T cell infiltration that correlate with disease severity. However, the absence of CD8 + predominance suggests limitations of this model for dissecting CD8 + T cell-specific contributions to LN pathogenesis. Yet, these findings underscore the need to identify renal antigens driving CD8 + T cell responses in human LN.