LAG3, short for Lymphocyte Activation Gene-3, works to suppress an immune response by action to Tregs as well as direct effects on CD8+ T cells.
Lymphocyte activation gene 3（LAG-3）is an important immunosuppressive molecule, mainly expressed on the surface of activated T cells, similar to CD4 molecule structure, and highly binding to major histocompatibility complex (MHC-Ⅱ). It can negatively regulate the proliferation and function of T lymphocytes and maintain the stability of its internal environment.
Structure of LAG-3 molecule
LAG-3 is a transmembrane glycoprotein, which belongs to the immunoglobulins superfamily. It consists of three parts: extracellular region, transmembrane region and cytoplasmic region. The major histocompatibility complex is a ligand of LAG-3. The mature LAG-3 molecule consists of 470 amino acids with the relative molecular weight of 70,000. LAG-3 exists in the form of dimer or oligomer. LAG-3 was also expressed on the surface of NK cells.
Negative regulation of T cells by LAG-3 molecule
LAG-3 molecule can negatively regulate the proliferation and function of activated T cells and maintain the stability of T cells in the environment. On the surface of all T lymphocytes, TCR-CD3 complex T lymphocytes recognize antigens by binding TCR to antigenic epitopes of antigens, and pass activation signal LAG-3 to T cells through CD3 molecules as immunosuppressive molecules. By binding to TCR-CD3 complex, blocking the signal transduction between CD3/TCR and TCR-mediated calcium flow, and inhibiting TCR-CD3 complex, the complexes are involved in antigen recognition and activation signal transmission of T cells.
LAG-3 molecules inhibit immune response by acting on Tregs cells. High expression of LAG-3 was found on the surface of Treg cells. By enhancing the inhibitory function of Treg cells and indirectly regulating the proliferation and function of activated T cells, it was found that LAG-3 expressed on Treg cells could bind to MHC-Ⅱ molecules on dendritic cells (DC) membrane. It inhibited the maturation of DC and induced the formation of tolerant DC, which further inhibited the activation and proliferation of T cells.
Expression of LAG-3 molecules in chronic viral infectious diseases
In the process of chronic virus infection, the anti-virus T cell response can not effectively control virus replication and eliminate virus, the main reason is the depletion of anti-virus CD8+ and CD4+ T cells. T cell depletion refers to the loss of T cell function in patients with common chronic infection and cancer. T cell depletion is the main reason why antiviral T cell response can not effectively control virus replication and eliminate virus. LAG-3 as an immunosuppressive molecule can cause depletion of T cell function during chronic viral infection.
LAG-3 target drug
Therapeutic drugs targeting LAG-3 have been vigorously developed, one of the most important of which is IMP321. IMP321 enhances the immune response to tumor cells through two different mechanisms. IMP321 combined with MHC-II molecules on immature DC cells to promote the maturation of DC cells and to enhance antigen presentation. IMP321 also blocked the binding of MHC-II molecules to LAG-3 expressed by CD8+ T cells, thus removing the inhibitory effect of T cell activation.
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Ma Chenyun, Lu Zhicheng, Shen Qian.(2015).The immunosuppression of lymphocyte activation gene 3 and its effects in chronic viral infection. Laboratory Medicine.30(3),298-302