Panel A: Autoreactive T cell expressing the receptors CTLA-4, PD-1, LAG3, TIM-3, and TIGIT having a pro-inflammatory response and promoting tissue damage. Panel B: Autoreactive T cell with agonist antibodies targeting IRs reducing inflammation and tissue damage. Panel C: Targeting CTLA-4, LAG3, TIM-3, and TIGIT with agonist abs on regulatory T cells (Tregs) increases stability and suppressive function, inducing an anti-inflammatory response and reducing tissue damage. Panel D: Targeting PD-1 and LAG3 on Tregs with agonist abs may decrease proliferation and suppression, causing a pro-inflammatory response with increased tissue damage. Depending on the disease and tissue, LAG3 can stimulate or inhibit Treg function.
Differential effects of IR agonism on Teffs and Tregs in autoimmune diseases. (A–D) Pathogenic autoreactive T cells express multiple IRs, and agonist Abs targeting these IRs can suppress effector T cell (Teff) responses to reduce autoimmune inflammation. However, many IRs are also expressed on Tregs, which are critical for maintaining immune tolerance. The impact of IR agonism on Tregs is receptor dependent: signaling through CTLA-4, TIM-3, and TIGIT supports Treg stability and function, whereas PD-1 engagement decreases Treg suppressive capacity. In contrast, LAG3 activity appears to be context dependent, varying by disease state and tissue environment. Consequently, the overall therapeutic outcome depends on whether the balance between Teff inhibition and Treg preservation is maintained. Emerging strategies, such as bsAbs or cell type–restricted agonists, aim to preferentially target pathogenic Teffs while minimizing off-target effects on Tregs. The figure was created with BioRender.