Autoreactive T cells target peripheral nerves in Guillain–Barré syndrome

• Published in: Nature (London) Vol. 626; no. 7997; pp. 160 - 168
• Main Authors: Súkeníková, L., Mallone, A., Schreiner, B., Ripellino, P., Nilsson, J., Stoffel, M., Ulbrich, S. E., Sallusto, F., Latorre, D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2024; Nature Publishing Group
• Subjects: 13; 13/21; 13/31; 45; 45/23; 45/91; 631/250/1619/554; 631/250/1619/554/1775; 631/250/371; 631/250/38; 692/699/249/1313; Antigens; Autoimmune diseases; Biomedical materials; Biopsy; Blood; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - pathology; Cerebrospinal fluid; Cloning; COVID-19; Cytomegalovirus; Cytotoxicity; Demyelinating diseases; Demyelination; Disease; Epitopes; Gene sequencing; Genes; Genotype & phenotype; Guillain-Barre syndrome; Guillain-Barre Syndrome - etiology; Guillain-Barre Syndrome - pathology; Humanities and Social Sciences; Humans; Immunodominance; Immunological memory; Infections; Inflammation; Influenza; Lymphocytes; Lymphocytes T; Memory cells; multidisciplinary; Myelin; Nervous system; Neuropathy; Pathophysiology; Patients; Peripheral nerves; Peripheral Nerves - pathology; Peripheral nervous system; Peripheral Nervous System Diseases - complications; Peripheral neuropathy; Phenotypes; Proteins; Receptors, Antigen, T-Cell; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; T cell receptors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06916-6

Guillain–Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness 1 . Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4 + cells, that show a cytotoxic T helper 1 (T H 1)-like phenotype, and rare CD8 + T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3β lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRβ clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications. Autoreactive T cells that target myelin antigens in the peripheral nerves are present in patients with the demyelinating form of Guillain–Barré syndrome, and these T cells are likely to contribute to disease pathophysiology.