Cytokine-mediated activation of kidney-infiltrating CD8⁺ T cells enables their contribution to inflammation in human lupus nephritis

Skopnik CM, Klocke J, Freund P, Metzke D, Ostendorf L, Bunse M, Prskalo L, Kotzbauer J, Hinze C, Grothgar E, Goerlich N, Wagner L, Daniel C, Hartmann A, Schneider U, Biesen R, Alexander T, Hauser AE, Radbruch A, Eckardt KU, Hiepe F, Kruglov A, Mashreghi MF, Enghard P (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 18

Article Number: eadz2015

Journal Issue: 857

DOI: 10.1126/scitranslmed.adz2015

Abstract

Proliferative lupus nephritis (LN) is triggered by deposition of autoantibodies in glomeruli and paralleled by a T cell-rich kidney infiltrate. Although these T cells have been attributed to the propagation of tissue injury, it is unclear how they are activated and whether T cell autoreactivity drives local inflammation. Kidney-infiltrating T cells are also observed in urine, where they have high resemblance to interstitial T cells. Therefore, urinary T cells are a proxy for investigating tissue pathogenesis. Here, we analyzed urinary T cells to elucidate whether a kidney-specific T cell autoimmune reaction contributes to tubulointerstitial inflammation in LN. Using single-cell RNA sequencing, we compared transcriptomes and clonotypes of T cells from the blood and urine of patients with active LN and showed that urinary T cells were mostly activated CD8 effector memory cells recruited from a circulating CX3CR1+ subset. Several urinary CD8 T cell clones were expanded. However, upon in vitro testing of their T cell receptors, we did not observe autoreactivity against autologous tubular epithelial cells. Instead, ≈ 20 of expanded clonotypes were Epstein-Barr virus-specific or cytomegalovirus-specific, but respective viral antigens were undetectable in kidney biopsies or urine. Conversely, kidney-infiltrating T cells had access to interleukin-15 and interferon-β (IFN-β), and stimulation with these cytokines was sufficient to trigger degranulation and production of tumor necrosis factor, IFN-γ, and granzyme K. Together, these results show that CD8+CX3CR1+ T cells are recruited into the kidney in LN, where they are activated by cytokines, enabling them to contribute to local inflammation.

Authors with CRIS profile

Christoph Daniel Department of Nephropathology Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie

Involved external institutions

Charité - Universitätsmedizin Berlin DE Germany (DE) Deutsches Rheuma-Forschungszentrum (DRFZ) DE Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft / Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) DE Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE)

How to cite

APA:

Skopnik, C.M., Klocke, J., Freund, P., Metzke, D., Ostendorf, L., Bunse, M.,... Enghard, P. (2026). Cytokine-mediated activation of kidney-infiltrating CD8⁺ T cells enables their contribution to inflammation in human lupus nephritis. Science Translational Medicine, 18(857). https://doi.org/10.1126/scitranslmed.adz2015

MLA:

Skopnik, Christopher M., et al. "Cytokine-mediated activation of kidney-infiltrating CD8⁺ T cells enables their contribution to inflammation in human lupus nephritis." Science Translational Medicine 18.857 (2026).

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