Dysregulated CSF T-cell responses and their evolution after intravenous immunoglobulin in Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an acute immune-mediated neuropathy that frequently results in long-term disability.

The cellular mechanisms underlying GBS and the immunomodulatory effects of intravenous immunoglobulin (IVIg) remain incompletely understood. In this prospective observational cohort study, we performed single-cell RNA sequencing with paired T cell receptor (TCR) sequencing on peripheral blood and cerebrospinal fluid (CSF) collected before and after IVIg treatment from treatment-naïve patients with GBS.

Pre-treatment blood and CSF were obtained from nine and eight patients, respectively; post-treatment samples were available from six patients for blood and three patients for CSF. Previously published healthy control (HC) blood and CSF single-cell datasets were analyzed for comparison.

We characterized immune cell composition, transcriptional states, TCR clonality, and clonal dynamics across peripheral and CSF compartments as well as following treatment. Individuals with GBS exhibited enrichment of T helper 1 (Th1)-polarized CD4+ T cells, activated and resident-memory CD8+ T cells, and macrophages in CSF relative to paired peripheral blood.

This CSF-to-blood enrichment was greater than in healthy controls (HCs) for Th1 cells, activated effector-memory CD8+ T cells, and inflammatory macrophages, although the overall degree of T-cell clonal expansion was similar between groups. In both GBS and HCs, expanded CSF CD4+ clonotypes were predominantly Th1-polarized and largely absent from blood, whereas expanded CD8+ clonotypes showed greater overlap between compartments.

Among clonotypes detected in both blood and CSF, CD4+ and CD8+ T cells exhibited more activated transcriptional states in the CSF, a shift that was particularly pronounced in GBS.

Among clonotypes detected in both blood and CSF, CD4+ and CD8+ T cells exhibited more activated transcriptional states in the CSF, a shift that was particularly pronounced in GBS.

Following IVIg treatment, peripheral blood showed minimal changes, whereas CSF T-cell populations exhibited more substantial alterations, including reductions in Th1-associated and activated effector-memory states, increases in T helper 2 (Th2) and regulatory T cell populations, and changes in the clonal repertoire. Expanded T cell clonotypes with sequence-based predicted specificity for pathogens associated with GBS were identified in six patients, and convergent clonotype groups were detected both within and across patients.

Demyelinating GBS is characterized by compartmentalized enrichment and activation of pro-inflammatory T-cell populations within the CSF rather than an overall increase in T-cell clonal expansion. Exploratory longitudinal findings further suggest that CSF T-cell populations are altered following IVIg treatment.

Integrated single-cell transcriptomic and TCR analyses provide insight into the early immune response in GBS and identify candidate cellular pathways for biomarker development and therapeutic investigation.