Lymphocyte-activation gene 3

Overview

CD4 and LAG-3 with opposing functions

Lymphocyte-activation gene 3 (LAG-3), also known as CD223, is a protein that in humans is encoded by the LAG3 gene. It is a member of the immunoglobulin superfamily and is expressed on the surface of activated T cells, natural killer (NK) cells, B cells, and plasmacytoid dendritic cells. LAG-3 plays a critical role in the regulation of the immune response, acting as an immune checkpoint receptor that modulates T cell function.

Structure

LAG-3 is a type I transmembrane protein consisting of four extracellular immunoglobulin-like domains (D1-D4), a transmembrane domain, and a short cytoplasmic tail. The extracellular domains are responsible for binding to its ligands, while the cytoplasmic tail is involved in signal transduction. The structure of LAG-3 is similar to that of CD4, a co-receptor for the T cell receptor (TCR), but LAG-3 has distinct functions in immune regulation.

Function

LAG-3 functions primarily as a negative regulator of T cell activation and proliferation. It is upregulated on activated T cells and functions to dampen the immune response, preventing excessive activation that could lead to autoimmunity. LAG-3 achieves this by competing with CD4 for binding to major histocompatibility complex (MHC) class II molecules, thereby inhibiting TCR signaling. Additionally, LAG-3 can interact with other ligands, such as galectin-3 and liver sinusoidal endothelial cell lectin (LSECtin), contributing to its immunosuppressive effects.

Role in Disease

LAG-3 is implicated in various diseases, particularly in cancer and autoimmune disorders. In cancer, LAG-3 expression is often upregulated on tumor-infiltrating lymphocytes, where it contributes to the immune evasion of tumors by inhibiting effective anti-tumor T cell responses. This has made LAG-3 a target for cancer immunotherapy, with several LAG-3 blocking antibodies currently in clinical trials.

In autoimmune diseases, LAG-3's role as an immune checkpoint can be beneficial by preventing overactive immune responses that damage host tissues. However, dysregulation of LAG-3 expression or function can contribute to the pathogenesis of autoimmune conditions.

Therapeutic Target

Given its role in modulating immune responses, LAG-3 is a promising target for therapeutic intervention. In cancer, LAG-3 inhibitors are being developed to enhance T cell activity against tumors. These inhibitors are often used in combination with other immune checkpoint inhibitors, such as PD-1 or CTLA-4 blockers, to improve therapeutic efficacy.

In autoimmune diseases, strategies to enhance LAG-3 function or mimic its activity are being explored to suppress pathological immune responses. The dual role of LAG-3 in both promoting immune tolerance and limiting anti-tumor immunity highlights the complexity of targeting this molecule in different disease contexts.

Related pages

• Immune checkpoint
• T cell
• Cancer immunotherapy
• Autoimmune disease