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<p>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 <i>IKZF2</i> gene; by contrast, these cells show activated TCR signaling and increased <i>TNF</i> and <i>IFNG</i> gene expression. Importantly, Ri-AIE-derived KIR<sup>+</sup>CD8<sup>+</sup> T cells from blood also express higher levels of <i>TOX</i>, 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Sylvain Perriot,
  • Samuel Jones,
  • Raphaël Genolet,
  • Amandine Mathias,
  • Helen Lindsay,
  • Sara Bobisse,
  • Giovanni Di 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,
  • Renaud Du Pasquier

摘要

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.