Activated αβ T- and reduced mucosa-associated invariant T cells in LGI1- and CASPR2-encephalitis.

Anti-Leucine-rich glioma inactivated-1 (LGI1) and anti-contactin-associated-protein-2 (CASPR2) autoimmune encephalitis (AIE) are common and characterized by pathogenic antibodies targeting neuronal autoantigens. However, the drivers of the antibody-secreting cells (ASC) and involvement of T cells remain unresolved. We performed single cell RNA-sequencing of fresh cerebrospinal fluid (CSF) and parallel blood samples of 15 patients with LGI1- (n=9) and CASPR2-AIE (n=6) compared to control patients (multiple sclerosis (MS) n=15, idiopathic intracranial hypertension (IIH) n=18). We validated our observations in independent cohorts using flow cytometry of CSF and blood. We confirmed autoantibody specificity using recombinant human monoclonal antibodies. Compared to IIH and MS controls, we observed clonal CSF-specific ASC expansion in LGI1/CASPR2-AIE despite mostly normal CSF findings. ASCs were dominantly plasmablasts and transcribed IgG4 and IgG1/2 heavy chains. Expanded clones showed signs of affinity maturation and bound the respective neuronal autoantigen. Within CD4 and CD8 T cell clusters, CD4 and CD8 central memory T cells were activated, clonally restricted and expanded. T cell clones were often shared between CSF and blood. We also observed a shift of NK cells and loss of mucosa-associated invariant T (MAIT) cells in the CSF of LGI1- and blood of LGI1- and CASPR2-AIE compared to IIH and MS controls. Indeed, MAIT-like T cells were detected in autopsy brains of LGI1 and CASPR2-AIE patients and mice lacking MAIT cells displayed an increased antibody seroconversion and higher titers following active LGI1-/CASPR2 immunization. Our data (1) confirms the intrathecal antigen-specific plasma cell expansion in LGI1- and CASPR2-AIE in a large cohort of untreated AIE patients, (2) suggests that activated and expanded central memory CD4 and CD8 T cells in the CSF participate in disease pathogenesis and (3) for the first time implicates invariant T cell receptor expressing lymphocytes in the brain, CSF and blood in disease pathogenesis. o̧pyright The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.