Soluble LAG-3 Identifies a Dynamic Early T Cell Activation Window in self-reactivity, Type 1 Diabetes, and Broader Immune Responses

<b>What is already known about this subject?:</b> Before the clinical onset of hyperglycemia, type 1 diabetes is characterized by a prolonged preclinical phase in which autoreactive B and T cells mediate progressive beta-cell destruction.Current risk stratification strategies rely mainly on genetic susceptibility (genomic DNA) and the detection of islet autoantibodies in plasma/serum.Islet autoantibodies arise only after CD4⁺ T cell activation and therefore do not capture the earliest stages of immune dysregulation.Consequently, biomarkers that directly reflect early pathogenic T cell activity prior to, or independent of, seroconversion remain limited and insufficiently validated.<b>What is the key question?:</b> Can plasma sLAG-3 levels, beta-cell antigen-specific CD4⁺ T cell tetramer expression, and circulating <i>Ins2</i> mRNA serve as very early biomarkers of autoimmune activity in type 1 diabetes and serve to better inform risk stratification, thereby informing preventive intervention strategies for the clinician? <b>What are the new findings?:</b> sLAG-3 increases transiently during early antigen-specific CD4⁺ T cell activation stage, precedes hyperglycemia in mouse models, and is elevated in autoantibody-negative and single-autoantibody-positive first-degree relatives who later progress to type 1 diabetes. sLAG-3 was associated with beta-cell antigen-specific CD4⁺ T cell expansion, assessment of stress induced beta cell <i>Ins2</i> mRNA release and high-risk HLA genotypes, indicating early autoimmune activation rather than established disease. <b>How might this impact clinical practice in the foreseeable future?:</b> These findings support sLAG-3 as a candidate early biomarker of T cell activation, before or at the earliest stages of islet autoantibody development in some at-risk individuals. Integration of plasma sLAG-3 with beta-cell antigen specific CD4⁺ T cell profiling and insulin mRNA measurements could complement current autoantibody-based screening, improve risk stratification, and enable earlier preventive interventions to preserve beta-cell function in patients at-risk for type 1 diabetes.