LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes

Area of Science:

• Immunology
• Cell Biology
• Autoimmunity

Background:

• Inhibitory receptors (IRs) regulate T cell homeostasis, but their function on regulatory T cells (Tregs) is unclear.
• IRs on Tregs may be crucial for suppressive activity or could limit Treg function.

Purpose of the Study:

• To investigate the role of lymphocyte activation gene 3 (LAG3) on Tregs in a murine model of type 1 diabetes.
• To determine if LAG3 expression on Tregs influences autoimmune disease development, Treg proliferation, and function.

Main Methods:

• Generated mice lacking LAG3 specifically on Tregs in a type 1 diabetes model.
• Analyzed transcriptional landscapes of wild-type (WT) and LAG3-deficient Tregs.
• Performed cotransfer experiments comparing WT and LAG3-deficient Tregs in islets and periphery.

Main Results:

• Mice lacking LAG3 on Tregs showed reduced autoimmune diabetes, indicating enhanced Treg function.
• LAG3-deficient Tregs outcompeted WT Tregs in islets due to increased IL-2 signaling and Eos expression.
• Transcriptional differences were observed in intra-islet Tregs, affecting maintenance and function.

Conclusions:

• LAG3 intrinsically limits Treg proliferation and function at inflammatory sites.
• LAG3 promotes autoimmunity in chronic autoimmune-prone environments.
• LAG3 may contribute to Treg insufficiency in autoimmune diseases.