Type I interferon drives T cell cytotoxicity by upregulation of interferon regulatory factor 7 in autoimmune kidney diseases in mice

Huiying Wang, Jonas Engesser, Robin Khatri, Darius P. Schaub, Hans-Joachim Paust, Zeba Sultana, Saskia-Larissa Jauch-Speer, Anett Peters, Anna Kaffke, Stefan Bonn, Tobias B. Huber, Hans-Willi Mittrücker, Christian F. Krebs, Ulf Panzer () and Nariaki Asada ()
Additional contact information
Huiying Wang: University Medical Center Hamburg-Eppendorf
Jonas Engesser: University Medical Center Hamburg-Eppendorf
Robin Khatri: University Medical Center Hamburg-Eppendorf
Darius P. Schaub: University Medical Center Hamburg-Eppendorf
Hans-Joachim Paust: University Medical Center Hamburg-Eppendorf
Zeba Sultana: University Medical Center Hamburg-Eppendorf
Saskia-Larissa Jauch-Speer: University Medical Center Hamburg-Eppendorf
Anett Peters: University Medical Center Hamburg-Eppendorf
Anna Kaffke: University Medical Center Hamburg-Eppendorf
Stefan Bonn: University Medical Center Hamburg-Eppendorf
Tobias B. Huber: University Medical Center Hamburg-Eppendorf
Hans-Willi Mittrücker: University Medical Center Hamburg-Eppendorf
Christian F. Krebs: University Medical Center Hamburg-Eppendorf
Ulf Panzer: University Medical Center Hamburg-Eppendorf
Nariaki Asada: University Medical Center Hamburg-Eppendorf

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and systemic lupus erythematosus (SLE), glomerulonephritis is a severe kidney complication driven by immune cells, including T cells. However, the mechanisms underlying T cell activation in these contexts remain elusive. Here we report that in patients with AAV and SLE, type I interferon (IFN-I) induces T cell differentiation into interferon-stimulated genes-expressing T (ISG-T) cells, which are characterized by an elevated IFN-I signature, an immature phenotype, and cytotoxicity in inflamed tissue. Mechanistically, IFN-I stimulates the expression of interferon regulatory factor 7 (IRF7) in T cells, which in turn induces granzyme B production. In mice, blocking IFN-I signaling reduces IRF7 and granzyme B expression in T cells, thus ameliorating glomerulonephritis. In parallel, spatial transcriptomic analyses of kidney biopsies from patients with AAV or SLE reveal an elevated ISG signature and the presence of ISG-T cells in close proximity to plasmacytoid dendritic cells, the primary producers of IFN-I. Our results from both patients and animal models thus suggest that IFN-I production in inflamed tissue may drive ISG-T cell differentiation to expand the pool of cytotoxic T cells in autoimmune diseases.

Date: 2025
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DOI: 10.1038/s41467-025-59819-7

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