Leveraging a naturally occurring IgM autoantibody to target diabetogenic T cells: a precision medicine approach to type 1 diabetes.

Current immunotherapies for autoimmune diseases lack sufficient specificity and often compromise protective immunity, underscoring the need for precision-based approaches. Here, we identify x-mAb, a germline-encoded IgM autoantibody derived from dual-expresser lymphocytes of patients with type 1 diabetes (T1D), as a potent agent for precision immunotherapy. In the nonobese diabetic mouse model, x-mAb prevents disease onset, induces durable remission, and preserves functional pancreatic islets without disrupting systemic immune homeostasis. Mechanistically, x-mAb selectively targets islet-reactive CD4 and CD8 tissue-resident memory (Trm) T cells in pancreas and pancreatic lymph nodes, as shown by MHC tetramer staining and in vivo tracking. x-mAb engagement downregulates CD69, a key Trm retention molecule, resulting in a marked reduction of pathogenic pancreatic T cells. Critically, x-mAb recognizes analogous CD69+ Trm-like peripheral T cells in T1D patients and downregulates CD69 ex vivo, indicating a conserved and therapeutically targetable mechanism across species. Structural modeling revealed that x-mAb engages TCRαβ through multiple contact sites, with the most stable interactions targeting a conserved CDR3α SGGGGS motif shared by diabetogenic human and mouse clonotypes. Based on these findings, we propose natural IgM autoantibodies as a previously unrecognized reservoir for precision biologics that selectively target autoreactive T cells while preserving immune competence.