Associate Professor of Pathology Johns Hopkins University Baltimore, Maryland, United States
Introduction/Rationale: Type 1 Diabetes (T1D) results from autoreactive T cell-mediated destruction of β cells. These rare T cells resemble conventional T cells and recognize diverse autoantigens, making detection difficult. Current therapies, like anti-CD3 or anti-CD20, broadly suppress immunity, causing toxicity and limited durability. We identified x-mAb, a germline-encoded IgM autoantibody from a T1D patient, with unique properties: it is a “public” autoantibody, independently generated across patients, and produced by dual-expresser CD5⁺CD19⁺ B cells co-expressing BCR and TCR genes, enriched for autoreactive IgM. These features suggest x-mAb could enable system-level detection and tolerization of autoreactive T cells.
Methods: x-mAb binding was evaluated in human and NOD mouse T cells, including insulin- and GAD65-specific CD8⁺ cells. Molecular dynamics modeled x-mAb–TCRα interactions. Repeated x-mAb dosing was tested for tolerization in diabetic NOD mice.
Results: x-mAb demonstrates strong disease-driven selection, enrichment in natural autoreactive IgM from DE B cells, and specific marking of autoreactive T cells in humans and NOD mice. Simulations confirm direct binding to TCRα motifs linked to insulin reactivity. x-mAb marks a conserved, disease-relevant T cell subpopulation in both humans and NOD mice, including insulin- and GAD65-specific CD8⁺ T cells. Notably, x-mAb administration induces robust, durable remission in diabetic NOD mice, consistent with antigen-specific tolerization, highlighting its potential as a first-in-class tool for system-level detection and modulation of autoreactive T cells.
Conclusion: x-mAb provides a first-in-class tool for system-level detection and selective modulation of autoreactive T cells. These findings establish a framework for precise immunotherapy in T1D that avoids global immune suppression and offers mechanistic and translational insight.
