LAG3 - lymphocyte activating 3 |Elisa - Clia - Antibody - Protein

Background

LAG-3 (lymphocyte-activation gene 3), also known as CD223, is a cell surface protein that plays a critical role as an immune checkpoint inhibitor. It functions as a negative regulator of T cell activity and is predominantly expressed on activated T cells, regulatory T cells (Tregs), and natural killer (NK) cells. LAG-3 belongs to the immunoglobulin (Ig) superfamily and is structurally similar to CD4, although it performs an inhibitory rather than activating function. Its primary ligand is the major histocompatibility complex (MHC) class II, and it binds with much higher affinity than CD4, providing it with strong immunoregulatory capabilities.

As an immune checkpoint receptor, LAG-3 is critical for maintaining immune homeostasis and preventing autoimmune reactions by moderating immune responses. Its expression is upregulated during chronic infections and in cancer, often contributing to T cell exhaustion, a state in which T cells progressively lose function due to prolonged antigen exposure. This makes LAG-3 a therapeutic target in immuno-oncology and chronic infection therapies. The blockade of LAG-3 has shown potential in restoring T cell function, thereby enhancing anti-tumor and anti-pathogen immune responses.

Protein Structure

LAG-3 is a type I transmembrane glycoprotein with distinct structural domains:

Extracellular Domain:

• The extracellular domain of LAG-3 consists of four Ig-like domains (D1–D4). The D1 domain is the primary binding site for MHC class II molecules, which is key for LAG-3’s function as an immune checkpoint.
• The D1 domain contains a unique extra loop structure stabilized by disulfide bonds, differentiating it from CD4 and enhancing its MHC II binding affinity. This feature provides LAG-3 with its high affinity for MHC II and allows it to effectively inhibit T cell activation.
• Each Ig-like domain is essential for stabilizing the extracellular structure, and specific residues within the D1 domain interact directly with MHC II molecules.

Transmembrane Domain:

• The transmembrane domain anchors LAG-3 within the cell membrane, maintaining its stability and enabling effective ligand binding.
• Although the transmembrane region does not contain intrinsic signaling motifs, it facilitates interactions with intracellular adaptor proteins that transmit downstream inhibitory signals.

Cytoplasmic Tail:

• The cytoplasmic tail is relatively short but contains two key functional motifs. The KIEELE motif is unique to LAG-3 among immune checkpoint receptors and is crucial for its inhibitory function. This motif is thought to mediate interactions with intracellular signaling molecules that transmit suppressive signals to the cell.
• Additionally, the cytoplasmic tail includes serine phosphorylation sites that, when phosphorylated, may alter LAG-3’s inhibitory activity or interactions with adaptor proteins.
• The exact mechanisms by which the KIEELE motif and phosphorylation sites modulate T cell signaling are still under investigation, but they are believed to be critical for the receptor's immunosuppressive effects.

Classification and Subtypes

LAG-3 is classified within the Ig superfamily, based on the Ig-like domains that characterize its structure. It is most closely related to CD4, sharing structural similarities but differing functionally. Although LAG-3 does not have distinct subtypes, its expression and function can vary across different immune cell types:

1. Activated T Cells: LAG-3 is upregulated on T cells upon activation, especially under chronic antigen exposure, such as in infections and tumors.
2. Regulatory T Cells (Tregs): LAG-3 expression on Tregs enhances their suppressive function, aiding in immune tolerance.
3. Natural Killer (NK) Cells: LAG-3 can also be expressed on NK cells, where it has been shown to regulate NK cell cytotoxic activity, though the exact mechanisms are less understood compared to T cell regulation.

Function and Biological Significance

LAG-3 acts as an immune checkpoint by transmitting inhibitory signals to immune cells, primarily T cells, through its interaction with MHC class II. This suppressive function helps regulate immune responses to maintain a balance between activation and tolerance. The functions of LAG-3 include:

Inhibition of T Cell Activation and Proliferation:

• By binding to MHC class II molecules on antigen-presenting cells (APCs), LAG-3 transmits inhibitory signals to T cells. This suppresses T cell receptor (TCR) signaling pathways, reducing T cell proliferation, cytokine production, and overall activation.
• This mechanism is important for preventing overactivation of the immune system, which could otherwise lead to tissue damage or autoimmune diseases.

Promotion of T Cell Exhaustion:

• LAG-3 is highly expressed in conditions of chronic antigen exposure, such as cancer or persistent infections. In these contexts, prolonged LAG-3 expression promotes T cell exhaustion, a state where T cells gradually lose their effector functions.
• T cell exhaustion is characterized by diminished cytokine production, proliferation, and cytotoxic activity, helping to limit immune responses to prevent excessive inflammation or tissue damage.

Modulation of Regulatory T Cell Activity:

• LAG-3 plays an important role on Tregs, where it enhances their immunosuppressive function. By increasing the activity of Tregs, LAG-3 promotes immune tolerance and prevents inappropriate immune responses against self-antigens.
• This function is crucial for maintaining tolerance and preventing autoimmune reactions.

Role in Immune Evasion by Tumors:

• Many tumors exploit LAG-3 to evade immune detection. By engaging LAG-3 on T cells within the tumor microenvironment, tumors can induce T cell exhaustion, effectively dampening the immune system's ability to recognize and kill cancer cells.
• In this context, blocking LAG-3 can reinvigorate exhausted T cells, restoring their cytotoxic activity against tumor cells.

Clinical Issues

Due to its role in immune regulation, LAG-3 has significant clinical implications, especially in the fields of cancer immunotherapy, autoimmune diseases, and chronic infections.

Cancer Immunotherapy:

• LAG-3 is a major target in cancer immunotherapy. Tumors can exploit LAG-3 to induce T cell exhaustion, allowing them to evade immune surveillance. LAG-3 inhibitors (such as monoclonal antibodies) are being developed to block this checkpoint, thereby restoring T cell function and enhancing anti-tumor responses.
• LAG-3 blockade is often combined with other checkpoint inhibitors, such as PD-1/PD-L1 blockers, to maximize anti-tumor immunity.

Autoimmune Disorders:

• Given its inhibitory effects on T cells, LAG-3 is being investigated as a therapeutic target for autoimmune diseases. Enhancing LAG-3 activity may help in conditions where the immune system mistakenly attacks healthy tissues, such as rheumatoid arthritis, type 1 diabetes, and lupus.
• Therapeutic strategies that enhance LAG-3 function or promote its expression on T cells and Tregs could suppress overactive immune responses, providing a potential treatment for autoimmune disorders.

Chronic Infections:

• In chronic infections, such as HIV or hepatitis, persistent antigen stimulation leads to T cell exhaustion. LAG-3 upregulation contributes to this exhausted state, limiting T cell effectiveness against the pathogen.
• Blocking LAG-3 in chronic infections is being explored as a strategy to rejuvenate exhausted T cells, potentially improving the immune system’s ability to control or eliminate the infection.

Summary

LAG-3 (lymphocyte-activation gene 3) is a critical immune checkpoint receptor that plays an inhibitory role in immune responses, especially in regulating T cell activation, proliferation, and function. Structurally, LAG-3 is a type I transmembrane glycoprotein with four extracellular Ig-like domains, a transmembrane region, and a cytoplasmic tail containing the KIEELE motif, essential for its immunosuppressive function. By binding MHC class II molecules on APCs, LAG-3 dampens T cell activation, prevents excessive immune responses, and promotes T cell exhaustion in chronic antigen exposure contexts.

The regulatory roles of LAG-3 in immune homeostasis make it a significant player in conditions such as cancer, autoimmune diseases, and chronic infections. Tumors often exploit LAG-3 to inhibit T cell activity, facilitating immune evasion. As a result, LAG-3 has become an important target in cancer immunotherapy, with LAG-3 inhibitors being developed to restore T cell function. In autoimmune diseases, enhancing LAG-3 function may help prevent excessive immune activation against self-antigens.

In summary, LAG-3 is essential for balancing immune responses, with therapeutic potential in both activating and inhibiting its function depending on the clinical context. Its unique structure and function make it a key focus in immunology and therapeutic research for diseases involving immune dysregulation.