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

Area of Science:

• Immunology
• Endocrinology
• Autoimmune Diseases

Background:

• Type 1 diabetes (T1D) involves autoimmune destruction of pancreatic beta-cells, leading to insulin deficiency.
• Current risk stratification relies on genetic factors and islet autoantibodies, which appear after T cell activation.
• There is a need for biomarkers reflecting early T cell activity to enable timely intervention.

Purpose of the Study:

• To investigate soluble Lymphocyte Activation Gene-3 (sLAG-3) as an early biomarker for T1D.
• To determine if sLAG-3 levels precede islet autoantibody development and correlate with T cell activation.
• To assess the potential of sLAG-3 for improved early risk stratification in T1D.

Main Methods:

• Longitudinal measurement of plasma sLAG-3 levels in NOD mice and human first-degree relatives (FDRs) of T1D patients.
• Analysis of sLAG-3 in relation to islet antigen-specific CD4+ T cell expansion and diabetes onset in murine models.
• Assessment of sLAG-3, beta-cell antigen-specific CD4+ T cell tetramer profiles, and circulating insulin (Ins2) mRNA in adoptive transfer models and human cohorts.

Main Results:

• Elevated sLAG-3 levels correlated with islet-specific CD4+ T cell expansion and preceded hyperglycemia in murine models.
• In adoptive transfer models, increased sLAG-3 and circulating Ins2 mRNA indicated immune activation and beta-cell stress before overt diabetes.
• In human FDRs, sLAG-3 was detected in autoantibody-negative and single-autoantibody-positive individuals, with higher levels in progressors and association with high-risk HLA genotypes.

Conclusions:

• sLAG-3 is a candidate biomarker for early T cell activation in T1D, potentially preceding islet autoantibody development.
• Integration of sLAG-3 with T cell and beta-cell stress markers could enhance early risk stratification for T1D.
• Further longitudinal studies are required to validate sLAG-3 as a surrogate marker for early T1D disease activity.