Neuron-reactive KIR+CD8+ T cells display an encephalitogenic transcriptional program in autoimmune encephalitis
Autoreactive CD8<sup>+</sup> T cells targeting neurons are the principal suspects in autoimmune encephalitis (AIE), but supporting data is still lacking. Here we identify neuron-reactive CD8<sup>+</sup> T cells in a cohort of six healthy donors and one patient with anti-Ri encephalitis (Ri-AIE) by querying natural antigen presentation of neurons that are derived from human induced pluripotent stem cells. Single-cell RNA sequencing of ex vivo CD8<sup>+</sup> T cells in an extended cohort of seven Ri-AIE patients and three aged-matched controls further reveal that these neuron-reactive CD8<sup>+</sup> T cells correspond to cytotoxic KIR<sup>+</sup>CD8<sup>+</sup> regulatory T cells. Intriguingly, KIR<sup>+</sup>CD8<sup>+</sup> T cells from most Ri-AIE patients have reduced expression of KIR and the key regulatory transcription factor, Helios, encoded by the IKZF2 gene; by contrast, these cells show activated TCR signaling and increased TNF and IFNG gene expression. Importantly, Ri-AIE-derived KIR<sup>+</sup>CD8<sup>+</sup> T cells from blood also express higher levels of TOX, a gene associated with encephalitogenic potential, and is expressed in cytotoxic CD8<sup>+</sup> T cells in the brain lesions of one Ri-AIE patient. Altogether, our data hints that dysregulated activity of neuron-reactive cytotoxic KIR<sup>+</sup>CD8<sup>+</sup> T cells may contribute to Ri-AIE pathogenesis.
Authors
- Samuel Jones (ORCID: https://orcid.org/0009-0003-2391-7997)
- Lise Queiroz
- Raphaël Gottardo (ORCID: https://orcid.org/0000-0002-3867-0232)
- Giovanni Di Liberto (ORCID: https://orcid.org/0000-0001-6788-0215)
- Ingrid Wagner (ORCID: https://orcid.org/0000-0003-4437-9799)
- Christophe Sauvage
- Marie Théaudin (ORCID: https://orcid.org/0000-0002-3026-3595)
- Alexandre Harari (ORCID: https://orcid.org/0000-0002-1055-2090)
- Marie Gimenez (ORCID: https://orcid.org/0009-0008-7048-5193)
- Heinz Wiendl (ORCID: https://orcid.org/0000-0003-4310-3432)
- Raphaël Genolet (ORCID: https://orcid.org/0000-0001-9335-3945)
- Mathieu Canales
- Sylvain Perriot (ORCID: https://orcid.org/0000-0002-0337-3262)
- Sara Bobisse (ORCID: https://orcid.org/0000-0002-3502-3224)
- Amandine Mathias (ORCID: https://orcid.org/0009-0005-3604-5096)
- Jérôme Honnorat (ORCID: https://orcid.org/0000-0002-4721-5952)
- Doron Merkler (ORCID: https://orcid.org/0000-0002-0247-2007)
- Renaud Du Pasquier (ORCID: https://orcid.org/0000-0002-2786-3434)
- Caroline Pot (ORCID: https://orcid.org/0000-0002-1146-3129)
- Helen Lindsay (ORCID: https://orcid.org/0000-0001-8614-1661)
- Larise Oberholster
- Diane Bégarie
- Stjepana Kovac (ORCID: https://orcid.org/0000-0002-5571-9237)
- Virginie Desestret
Institutions
- SIB Swiss Institute of Bioinformatics (CH)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University Medical Center Freiburg (DE)
- Centre Hospitalier Universitaire Vaudois (CH)
- Hospices Civils de Lyon (FR)
- University Hospital Münster (DE)
- University Hospital of Geneva (CH)
- Ludwig Cancer Research (CH)
- Geneva College (US)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1038/s41467-025-63573-1
- Citations
- 1
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- National Science Foundation
- Agence Nationale de la Recherche
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Centre Hospitalier Universitaire Vaudois