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bioRxiv · 10.1101/2025.11.03.685164

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

Montigny, P.·Aydin, S.·Maudoux, A.-L.·van Baren, N.·Brusa, D.·Dauguet, N.·Houssiau, F.·Lauwerys, B.·Coulie, P. G.
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Abstract

BackgroundLupus 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. MethodsWe 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. ResultsLupus-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. ConclusionsB6.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.

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Montigny, P., Aydin, S., Maudoux, A.-L., van Baren, N., Brusa, D., Dauguet, N., Houssiau, F., Lauwerys, B., Coulie, P. G.. 2025-11-04. CD8 T lymphocytes infiltrate the kidneys and correlate with disease progression in B6.NZMSle1/Sle2/Sle3 lupus mice. https://doi.org/10.1101/2025.11.03.685164

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