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LAG3/MHC Class II Signaling Pathway

Figure 1. LAG3/MHC class II signaling pathway

Introduction

Lymphocyte-activation gene 3, otherwise known as LAG-3, is a protein which in humans is encoded by the LAG3 gene which contains 8 exons. From the sequencing data, the composition of exons and introns and the location of the chromosomes all indicate that the relationship between LGA3 and CD4 is closely related. In human, the gene for LAG-3 lies adjacent to the gene for CD4 on chromosome 12 (12p13) and is approximately 20% identical to the CD4 gene, so it has the same ligand, MHC class II. LAG3, which was found in 1990 and was designated CD223 (cluster of differentiation 223) after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies aiming to develop new treatments for cancer and autoimmune disorders. In soluble form, it is also being developed as a cancer drug in its own right.

The function of pathway

The LAG3 protein, which belongs to immunoglobulin (Ig) superfamily, comprises a 503-amino acid type I transmembrane protein with four extracellular Ig-like domains, designated D1 to D4. According to previous studies, LAG-3 is expressed on activated T cells, natural killer cells, B cells and plasmacytoid dendritic cells. It's principal ligand is MHC class II, to which it binds with higher affinity than CD4. LAG3 was cloned over 20 years ago as a CD4 homologue, but its function in the immune checkpoint was only defined in 2005 when it turned out to have a role in enhancing the function of Treg cells(regulatory cells). The molecular pathways that mediate LAG-3 signaling are still largely unknown, although it is clear that the unique intracellular KIEELE domain is required for its function. In addition, analogous to immunosuppressive molecules, LAG-3 has also shown that it negatively regulates cellular proliferation, activation, and homeostasis of T cells, and it also helps maintain CD8+ T cells in a tolerogenic state and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection. Besides, LAG3 is considered to be involved in the maturation and activation of dendritic cells, and it also inhibits CD8+ effector T cell function independently of its role on Treg cells.For its ligand, MHC class II molecules, which are upregulated on some epithelial cancers (generally in response to IFNγ), are also expressed on tumour-infiltrating macrophages and dendritic cells. Although some articles have reported the part function ofLAG3, the role of the LAG3–MHC class II interaction in the LAG3-mediated inhibition of T cell responses is unclear because LAG3 antibodies that do not block the LAG3–MHC class II interaction nonetheless enhance T cell proliferation and effector cell functions in vitro and in vivo. This interaction may be most significant for the role of LAG3 in enhancing Treg cell function.

Clinical significance

There are 3 approaches involving LAG3 that are in clinical development. The first is a soluble LAG3 which activates dendritic cells (DC). It has been reported that LAG3 may be involved in the proinflammatory activity of cytokine-activated (Such as TNF-a and IL-12) bystander T cells and it may directly activate DC; the second is antibodies to LAG3 which take the brakes off the anti-cancer immune response. A number of additional LAG3 antibodies are currently in preclinical development. LAG-3 may be a better checkpoint inhibitor target than CTLA-4 or PD-1 since antibodies to these two checkpoints that only activate effector T cells, and do not inhibit Treg activity, whereas an antagonist LAG-3 antibody can both activate T effector cells (by downregulating the LAG-3 inhibiting signal into pre-activated LAG-3+ cells) and inhibit induced (i.e. antigen-specific) Treg suppressive activity. Despite this, we found that the anti-LAG-3 monoclonal antibody alone was not effective in treating tumors. This is because LAG-3 is one of various immune-checkpoint receptors that are coordinately upregulated on both Treg cells and anergic T cells, and simultaneous blockade of these receptors can result in enhanced reversal of this anergic state relative to blockade of one receptor alone. In particular, PD1 and LAG3 are commonly co-expressed on anergic or exhausted T cells. Dual blockade of LAG3 and PD1 synergistically reversed anergy among tumour-specific CD8+ T cells and virus-specific CD8+ T cells in the setting of chronic infection. Dramatic evidence of the effects of coordinate T cell inhibition by PD1 and LAG3 comes from Pd1–/–Lag3–/– double-knockout mice, which completely reject even poorly immunogenic tumours in a T cell-dependent manner but also develop autoimmune syndromes much more quickly than Pd1–/– or Lag3–/– single-knockout mice. Autoimmune syndromes in Pd1–/–Lag3–/– double-knockout mice are ultimately fatal, although they do not develop as quickly as in Ctla4-knockout mice. These findings emphasize the balance between anti-tumour effects and autoimmune side effects that must be considered in all of the immune-checkpoint-blockade strategies. The third is antibodies to LAG3 in order to blunt an autoimmune response.

Reference:

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