Pathogenic aquaporin-4 reactive T cells are sufficient to induce mouse model of neuromyelitis optica

Melina V. Jones, Hwa Huang, Peter A. Calabresi, Michael Levy

Neuromyelitis Optica (NMO) is an autoimmune disease primarily targeting the spinal cord and optic nerve leading to paralysis and blindness. The discovery of an antibody against the astrocytic water channel, aquaporin-4 (AQP4), in the majority of patients, has led to the presumption that the antibody was necessary for disease pathogenesis. The potential role of T cells in the central nervous system, however, has not been thoroughly examined. We generated an anti-AQP4 antibody seronegative model of NMO using pathogenic AQP4-reactive T cells in mice by immunizing AQP4 null mice with peptides corresponding to the second extracellular loop of AQP4, loop C. When polarized to a Th17 phenotype and transferred to wild-type mice, these cells caused tail and limb weakness. Histology showed demyelination and T cell infiltration in the spinal cord, optic nerve and brain. Animals receiving cells re-stimulated in culture with non-specific proteins resulted in no behavioral disease, indicating that specific targeting of AQP4 is essential for this phenotype. In summary, we show that AQP4-reactive T cells are sufficient to trigger an NMO-like disease in mice, independent of antibodies, indicating that pathogenic AQP4-reactive T cells may play a similar role in humans.