LAG3

Official Full Name

lymphocyte activating 3

Organism

Homo sapiens

GeneID

3902

Background

Lymphocyte-activation protein 3 belongs to Ig superfamily and contains 4 extracellular Ig-like domains. The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4. [provided by RefSeq, Jul 2008]

Synonyms

CD223;

Bio Chemical Class

Immunoglobulin

Protein Sequence

MWEAQFLGLLFLQPLWVAPVKPLQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILTYRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAPGALPAGHLLLFLILGVLSLLLLVTGAFGFHLWRRQWRPRRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPEQL

Open

Disease

Allergic/hypersensitivity disorder, Autoimmune disease, Brain cancer, Breast cancer, Diabetes mellitus, Lung cancer, Lymphoma, Malignant haematopoietic neoplasm, Melanoma, Psoriasis, Renal cell carcinoma, Solid tumour/cancer, Stomach cancer

Approved Drug

1 +

Clinical Trial Drug

15 +

Discontinued Drug

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Detailed Information

Recent Progress

Lymphocyte activation gene-3 (LAG3) is a protein with a high affinity for the CD4 receptor. It is expressed mainly by regulatory T cells with immunomodulatory functions(Fig. 1). LAG3 is a widely studied subject given that it is the third inhibitory receptor to be targeted in the clinic. Controlling overt activation and preventing the onset of autoimmunity require LAG3 upregulation. However, intriguingly, persistent antigen exposure in the tumor microenvironment leads to sustained LAG3 expression. The striking similarity between LAG3 and PD1 in several settings emphasizes the potential uniqueness of LAG3. There has already been four LAG3-targeted therapies in the clinic and many more are still preclinical trials. In order to understand the function of LAG3 during Mycobacterium tuberculosis (MTB) infection, researchers used a nonhuman primate model of tuberculosis. Results revealed that the expression of LAG3 is highly upregulated in the lungs, especially in the granulomatous lesions of macaques which were primarily infected with MTB. Moreover, it was indicated that, in the lungs and lung granulomas of animals exhibiting latent tuberculosis infection, LAG3 expression was not induced. The data collected is consistent with the finding that LAG3 expressed primarily on CD4(+) T cells, mainly by regulatory T cells but also by natural killer cells[1]. After generating mice in which LAG3 is absent on the cell surface of Tregs in a murine model of type 1 diabetes, investigators assessd the role of LAG3 on Tregs. According to the data, mice lacking LAG3 expression on Tregs displayed decreased autoimmune diabetes, consistent with enhanced Treg proliferation and function. LAG3-deficient Tregs outcompeted wild type Tregs in the islets but not in the periphery. This study demonstrates that LAG3 limits Treg proliferation and functions at inflammatory sites. It also enhances autoimmunity in a chronic autoimmune-prone environment. It has the potential to promote Treg insufficiency in autoimmune disease.

Fig. 1. Mechanism of LAG3. (James et al, 2009)

The potential mechanisms of action of the clinical agents that target the programmed cell death protein 1 (PD1) and LAG3 were also discussed by the researchers. Through an extensive review, it can be concluded that PD1 and LAG3 are expressed on 'exhausted' T cells. Though it would be worth mentioning that not all cells that express these receptors are exhausted. Moreover, triggering LAG3 on T cells by MHC class II ligands inhibits T cell function. IL-27 stimulation of Tregs could increase expression of LAG3. LAG3 expression in Tregs was important to modulate Treg function in suppressing colitogenic responses. These findings taken together highlight a novel role of the IL-27/Lag3 axis in modulating Treg regulation of inflammatory responses in the intestine. The effect of LAG3 on CD4+ CD25- T cells from non-small cell lung cancer (NSCLC) patients was also studied. Researchers discovered that LAG3 was significantly increased in CD4+ T cells, primarily in the CD4+ CD25- fraction, in the peripheral blood mononuclear cells of NSCLC patients. Compared with LAG3-nonexpressing CD4+ CD25- cells, CD4+ CD25- cells expressing LAG3 displayed significantly higher levels of PD1 and TIM3, which are also two inhibitory receptors. These cells also presented impaired proliferation compared with LAG3-nonexpressing CD4+ CD25– cells. However, they could be partially repaired by inhibiting both PD1 and TIM3. Co-culture with CD8+ T cell and LAG3-expressing CD4+ CD25- T cell tend to raise soluble IL-10 level in the supernatant, moreover, the concentration was positively correlated with the number of LAG3-expressing CD4+ CD25- T cells. These findings suggest that CD4+ CD25- T cells expressing LAG3 present another regulatory immune cell type with potential to interfere with anti-tumor immunity.

References:

Andrews, L. P., et al. "LAG3 (CD223) as a cancer immunotherapy target." Immunological Reviews 276.1(2017):80.
Phillips, B. L., et al. "LAG3 expression in active Mycobacterium tuberculosis infections. " American Journal of Pathology185.3(2015):820-33.
Zhang, Q., et al. "LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. " Science Immunology 2.9(2017):eaah4569.
Nguyen, L. T., and P. S. Ohashi. "Clinical blockade of PD1 and LAG3--potential mechanisms of action. " Nature Reviews Immunology15.1(2015):45-56.
Do, Jeongsu, et al. "An IL-27/Lag3 axis enhances Foxp3+ regulatory T cell suppressive function and therapeutic efficacy." Mucosal Immunology9.1(2016):137-145.
Ma, Q. Y., et al. "Function and regulation of LAG3 on CD4+CD25- T cells in non-small cell lung cancer. " Experimental Cell Research 360.2(2017).

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