Lymphocyte Activation Gene (LAG)-3 Is Associated With Mucosal Inflammation and Disease Activity in Ulcerative Colitis

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint on activated lymphocytes.
• LAG-3 expression is implicated in inflammatory processes.

Purpose of the Study:

• To investigate LAG-3 expression and function in immune cells from patients with ulcerative colitis (UC).
• To determine the role of LAG-3 in UC pathogenesis and its potential as a therapeutic target.

Main Methods:

• Flow cytometry, qRT-PCR, and single-cell RNA-sequencing were used to analyze LAG-3+ T cells.
• LAG-3+ cell frequencies were correlated with UC disease activity and endoscopic severity.
• Functional effects of LAG-3+ cells were assessed using a depleting anti-LAG-3 monoclonal antibody in a mixed lymphocyte reaction.

Main Results:

• LAG-3+ lymphocytes were significantly increased in inflamed UC mucosal tissue, correlating with disease severity.
• LAG-3 was predominantly expressed on effector memory T cells and activated cytokine-producing T cell subsets.
• LAG-3+ cell numbers decreased in patients responding to biologics, and anti-LAG-3 antibody treatment reduced T cell proliferation and IFNγ production.

Conclusions:

• Increased LAG-3+ cells in UC inflamed mucosa, particularly on activated effector memory T cells, correlate with disease activity.
• Depletion of LAG-3 effectively reduces activated proliferating T cells.
• LAG-3 represents a promising therapeutic target for ulcerative colitis.