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  3. AQP4-specific T cells determine lesion localization in the CNS in a model of NMOSD

AQP4-specific T cells determine lesion localization in the CNS in a model of NMOSD

  • Acta Neuropathol Commun. 2025 Feb 11;13(1):27. doi: 10.1186/s40478-025-01947-8.
Ali Maisam Afzali # 1 2,  Oleksii Ulianov # 1,  Luise Eckardt 1 2,  Ingrid Stas 1 2,  Lea Seeholzer 1,  Katja Steiger 3,  Doron Merkler 4,  Thomas Korn 5 6 7
Affiliations

Affiliations

  • 1 Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Ismaninger Str. 22, 81675, Munich, Germany.
  • 2 Department of Neurology, Technical University of Munich School of Medicine, Ismaninger Str. 22, 81675, Munich, Germany.
  • 3 Institute of Pathology, Technical University of Munich, Trogerstr. 18, 81675, Munich, Germany.
  • 4 Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, Centre Médical Universitaire, 1, Rue Michel Servet, 1211, Geneva, Switzerland.
  • 5 Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, Ismaninger Str. 22, 81675, Munich, Germany. thomas.korn@tum.de.
  • 6 Department of Neurology, Technical University of Munich School of Medicine, Ismaninger Str. 22, 81675, Munich, Germany. thomas.korn@tum.de.
  • 7 Munich Cluster for Systems Neurology, Feodor-Lynen-Str. 17, 81377, Munich, Germany. thomas.korn@tum.de.
  • # Contributed equally.
PMID: 39934927 DOI: 10.1186/s40478-025-01947-8
Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is a paradigmatic autoimmune disease of the central nervous system (CNS), in which the water channel protein Aquaporin-4 (AQP4) is targeted by a self-reactive immune response. While the immunopathology of human NMOSD is largely dependent on Antibodies to astrocytic AQP4, the role of AQP4-specific T cells for the localization and quality of NMOSD lesions in the CNS is not known. Only recently, we established that thymic B cells express and present AQP4 in the context of MHC class II molecules to purge the naive T cell receptor repertoire of AQP4-specific clones. Here, we exploited this finding to investigate the lesion localization in the CNS of B cell conditional AQP4-deficient (Aqp4ΔB) mice, which harbor AQP4-specific precursors in their naive T cell repertoire and can be sensitized to mount a strong AQP4(201-220)-specific CD4+ T cell response. Sensitization of Aqp4ΔB mice with AQP4(201-220) was sufficient to induce clinical disease. The spatiotemporal lesion distribution and the glial cell response in AQP4(201-220)-induced experimental autoimmune encephalomyelitis (EAE) was compared to classical MOG(35-55)-induced EAE in Aqp4ΔB mice. In contrast to MOG-EAE, AQP4(201-220)-induced EAE was characterized by midline lesions in the brain, retinal pathology, and lesions at the grey matter/white matter border zone in the spinal cord. Therefore, we conclude that antigen-specific T cells dictate the localization of NMOSD-lesions in the CNS.

Keywords

AQP4; Autoimmune astrocytopathy; EAE; MOG; NMOSD; T cells.

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