LAG3 (CD223) and autoimmunity: Emerging evidence

Immune checkpoint molecules play pivotal roles in maintaining the immune homeostasis. Targeting these molecules, such as the classical Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Cell Death Protein 1 (PD1), achieves great success in treating cancers. However, not all the patients respond well. This urges the immunologists to identify novel immune checkpoint molecules. Lymphocyte activation gene-3 (LAG3; CD223) is a newly identified inhibitory receptor. It is expressed on a variety of immune cells, including CD4+ T cells, CD8+ T cells, Tregs, B cells, and NK cells. Its unique intracellular domains, signaling patterns as well as the striking synergy observed in its targeted therapy with anti-PD1 indicate the important role of LAG3 in maintaining immune tolerance. Currently, a variety of agents targeting LAG3 are in clinical trials, revealing great perspectives in the future immunotherapy. In this review, we briefly summarize the studies on LAG3, including its structure, isoforms, ligands, signaling, function, roles in multiple diseases, as well as the latest targeted therapeutic advances, with particular concern on the potential association of LAG3 with autoimmune diseases. •LAG3 is a potential novel immune checkpoint molecule, exerting immunosuppressive functions in different immune cells.•Unique structure, isoforms, signaling and multiple ligands of LAG3 indicate its distinct and complex modes of action.•LAG3 is involved in different diseases, including autoimmune diseases, chronic infectious diseases and cancers.•Agents targeting LAG3 are in clinical trials for anti-tumor therapy, with perspectives in autoimmune disease application.