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

Author

Listed:
  • Sylvain Perriot

    (Lausanne University Hospital and University of Lausanne)

  • Samuel Jones

    (Lausanne University Hospital and University of Lausanne)

  • Raphaël Genolet

    (Agora Cancer Research Center
    Lausanne University Hospital and University of Lausanne-Ludwig Institute for Cancer Research)

  • Amandine Mathias

    (Lausanne University Hospital and University of Lausanne)

  • Helen Lindsay

    (Swiss Institute of Bioinformatics)

  • Sara Bobisse

    (Agora Cancer Research Center
    Lausanne University Hospital and University of Lausanne-Ludwig Institute for Cancer Research)

  • Giovanni Liberto

    (University and University Hospitals of Geneva
    University Hospital of Lausanne and Lausanne University Hospital)

  • Mathieu Canales

    (Lausanne University Hospital and University of Lausanne)

  • Lise Queiroz

    (Agora Cancer Research Center
    Lausanne University Hospital and University of Lausanne-Ludwig Institute for Cancer Research)

  • Christophe Sauvage

    (Agora Cancer Research Center
    Lausanne University Hospital and University of Lausanne-Ludwig Institute for Cancer Research)

  • 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
    Lausanne University Hospital and University of Lausanne-Ludwig Institute for Cancer Research)

  • Renaud Pasquier

    (Lausanne University Hospital and University of Lausanne
    University Hospital of Lausanne and Lausanne University Hospital)

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.

Suggested Citation

  • Sylvain Perriot & Samuel Jones & Raphaël Genolet & Amandine Mathias & Helen Lindsay & Sara Bobisse & Giovanni Liberto & Mathieu Canales & Lise Queiroz & Christophe Sauvage & Ingrid Wagner & Larise Obe, 2025. "Neuron-reactive KIR+CD8+ T cells display an encephalitogenic transcriptional program in autoimmune encephalitis," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63573-1
    DOI: 10.1038/s41467-025-63573-1
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