Neuron-reactive KIR+CD8+ T cells display an encephalitogenic transcriptional program in autoimmune encephalitis

Sylvain Perriot, Samuel Jones, Raphaël Genolet, Amandine Mathias, Helen Lindsay, Sara Bobisse, Giovanni Liberto, Mathieu Canales, Lise Queiroz, Christophe Sauvage, Ingrid Wagner, Larise Oberholster, Marie Gimenez, Diane Bégarie, Stjepana Kovac, Virginie Desestret, Marie Théaudin, Caroline Pot, Heinz Wiendl, Jérôme Honnorat, Doron Merkler, Raphaël Gottardo, Alexandre Harari and Renaud Pasquier ()
Additional contact information
Sylvain Perriot: Lausanne University Hospital and University of Lausanne
Samuel Jones: Lausanne University Hospital and University of Lausanne
Raphaël Genolet: Agora Cancer Research Center
Amandine Mathias: Lausanne University Hospital and University of Lausanne
Helen Lindsay: Swiss Institute of Bioinformatics
Sara Bobisse: Agora Cancer Research Center
Giovanni Liberto: University and University Hospitals of Geneva
Mathieu Canales: Lausanne University Hospital and University of Lausanne
Lise Queiroz: Agora Cancer Research Center
Christophe Sauvage: Agora Cancer Research Center
Ingrid Wagner: University and University Hospitals of Geneva
Larise Oberholster: Lausanne University Hospital and University of Lausanne
Marie Gimenez: Lausanne University Hospital and University of Lausanne
Diane Bégarie: Lausanne University Hospital and University of Lausanne
Stjepana Kovac: University Hospital Münster
Virginie Desestret: Inserm U1314/ UMR CNRS5284
Marie Théaudin: University Hospital of Lausanne and Lausanne University Hospital
Caroline Pot: University Hospital of Lausanne and Lausanne University Hospital
Heinz Wiendl: University Medical Center
Jérôme Honnorat: Inserm U1314/ UMR CNRS5284
Doron Merkler: University and University Hospitals of Geneva
Raphaël Gottardo: Swiss Institute of Bioinformatics
Alexandre Harari: Agora Cancer Research Center
Renaud Pasquier: Lausanne University Hospital and University of Lausanne

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

Abstract: Abstract Autoreactive CD8+ T cells targeting neurons are the principal suspects in autoimmune encephalitis (AIE), but supporting data is still lacking. Here we identify neuron-reactive CD8+ 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+ T cells in an extended cohort of seven Ri-AIE patients and three aged-matched controls further reveal that these neuron-reactive CD8+ T cells correspond to cytotoxic KIR+CD8+ regulatory T cells. Intriguingly, KIR+CD8+ 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+CD8+ T cells from blood also express higher levels of TOX, a gene associated with encephalitogenic potential, and is expressed in cytotoxic CD8+ T cells in the brain lesions of one Ri-AIE patient. Altogether, our data hints that dysregulated activity of neuron-reactive cytotoxic KIR+CD8+ T cells may contribute to Ri-AIE pathogenesis.

Date: 2025
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DOI: 10.1038/s41467-025-63573-1

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