Aquaporin-4-specific T cell responses in NMOSD revealed by mRNA-engineered dendritic cells

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system characterized by loss of immune tolerance to the water channel aquaporin-4 (AQP4). Current therapies do not specifically restore AQP4 tolerance or selectively suppress antigen-specific immune responses. Reprogramming patient's own dendritic cells (DCs) with mRNA to induce tolerance represents a promising therapeutic strategy. A key prerequisite for this approach is generating mRNAs encoding disease-relevant autoantigens recognized by the patient's immune system. Here, we generated recombinant mRNAs encoding human AQP4 and evaluated T cell responses to autologous DCs transfected with AQP4 mRNA in eight NMOSD patients and ten healthy controls. Transfected DCs were co-cultured with autologous T cells and stimulated twice. The assay detected robust AQP4-specific T cell response in a patient with recent disease activity who was not receiving immunosuppressive therapy, demonstrating its ability to identify clinically relevant autoreactive T cell responses. These findings establish the feasibility of an mRNA-based antigen-specific T cell assay for studying NMOSD pathogenesis, stratifying patients by T cell involvement, and supporting development of personalized tolerance-inducing therapies.