LAG-3 at the crossroads: A context-dependent regulator of Tregs and autoimmunity inflammatory disorders

This review aims to systematically examine the regulatory mechanisms of Lymphocyte Activation Gene 3 (LAG3) in modulating T regulatory cell (Treg) function and its context-dependent implications in major inflammatory and autoimmune diseases.

We conducted a comprehensive literature review synthesizing findings from basic research, preclinical animal models, and clinical studies investigating LAG3 expression and function across autoimmune conditions, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, autoimmune diabetes, inflammatory bowel disease, and psoriasis.

LAG3 exhibits dual, context-dependent roles in autoimmunity. In multiple sclerosis and rheumatoid arthritis, LAG3+ Tregs exert protective immunosuppressive functions via IL-10 and TGF-β. Conversely, in systemic lupus erythematosus and psoriasis, LAG3 expression can mark unstable Tregs transitioning to pathogenic IL-17-producing phenotypes. LAG3 also modulates Treg metabolic programming, IL-2/STAT5 signaling, and cooperates with other checkpoints like PD-1. Soluble LAG3 (sLAG-3) is elevated in several autoimmune diseases, but its functional significance remains unclear.

Understanding LAG3's context-dependent regulation of Tregs is crucial for developing precision immunotherapies. Future strategies should move beyond broad LAG3 blockade toward subset-specific modulation to restore immune tolerance in autoimmune diseases.