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

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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.

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