Guillain-Barré syndrome (GBS) is a rare heterogenous inflammatory peripheral neuropathy usually triggered by a preceding infection and causing a potentially life-threatening progressive muscle weakness. While the disease is generally considered to have an autoimmune basis, the underpinning immune-mediated mechanisms remain mostly elusive. This aspect poses a significant medical challenge in terms of accurate diagnosis, prognosis, and treatment. Building on our recent findings revealing that autoreactive T cell immunity play a key role in a subset of GBS patients, the project proposed herein aims at systematically elucidating its relative contribution to distinct GBS subtypes and disease stages. To this end, we will use cutting-edge technical approaches that enable the study of potentially rare autoreactive T cells in human biological samples (i.e. blood, cerebrospinal fluid and tissue biopsies) through three specific aims: Aim 1 is to perform in-depth immunophenotyping of blood-circulating immune cells for identification of potential variations in their frequency and distribution across GBS subtypes and stages; Aim 2 is to provide a systematic characterization of self-reactive T cells in patients’ biological samples by combining in vitro T cell screenings and ex vivo tetramers staining with high-throughput single cell analysis, such as single T cell clone generation, single cell RNA sequencing and TCR sequencing; Aim 3 is to dissect the cellular and molecular bases of cross-reactive T cell immunity in GBS by integrating in vitro sequential stimulation, single T cell clone generation and TCR sequencing with mass spectrometry-based immunopeptidomics or lipidomics. The outcomes of this project will significantly expand our understanding of the immunopathology of inflammatory peripheral neuropathies and advance our basic knowledge of human autoreactive T cell biology, with substantial implications for biomedical applications.