In vivo studies showed that NK cells from LAG-3 deficient mice show defects in the killing of specific cancer cells [21]. combination, which will provide data relating to the efficacy and security of proposed drug candidates. Keywords: LAG-3, novel anticancer therapies, numerous tumor types 1. Introduction Lymphocyte-activation gene 3 (LAG-3/CD223) is usually a 503 amino acid protein, localized in the cell membrane [1]. The extracellular part of the molecule consists of four immunoglobulin-like domains (D1-D4) The protein is usually encoded by the gene [2]. Its expression is usually regulated by IL-2, IL-7 and IL-12A/B on T cells [3]. Interestingly, the 8-exon-gene lies adjacent to the CD4 gene around the 12 chromosome (12: 6.77C6.78). The structural similarity of both genes is about 20% [4]. The protein biosynthesis product undergoes several modifications. These include the cleavage by ADAM10 and ADAM17 metalloproteinases, leading to the secretion of Secreted LAG-3 (sLAG-3). ADAM10 catalyzes constitutive cleavage induced by T cell activation [4]. However, ADAM17 activity enhances by T cell receptor (TCR) signaling in a PRKCQ-dependent manner. Besides, the protein is usually glycosylated on N250, N188, C256 and N343 amino acids. The antigen is an immune checkpoint receptor, which regulates T cell functions. Expressed on activated T cells, the antigen functions similarly to programmed death receptor-1 (PD-1) or cytotoxic T lymphocyte antigen-4 (CTLA-4) in the inhibition of cytotoxic cell function [5]. LAG-3 remains a ligand for the major histocompatibility complex (MHC) class II. Via the conversation, LAG-3 inhibits cellular proliferation and T cell activation [6]. The protein also binds to fibrinogen-like protein 1 (FGL1) in the MHC-II impartial pathway, which also delivers an inhibitory transmission. Besides, 3A9 cells expressing LAG-3 reduced IL-2 secretion upon treatment with FGL1 [7]. The other ligands for LAG-3 are LSECtin and Galectin-3 derived from tumor and tumor stromal cells, respectively. Both ligands lead to the reduction of IFN-gamma production in LAG-3 sufficient cells [8,9]. LAG-3 blockade has demonstrated the ability to enhance the efficacy of PD-1 blockade [10]. Physique 1 summarizes the molecular structure of LAG-3, as well as its interactions and regulations of LAG-3 expression. Open in a separate window Physique 1 (A) Molecular structure of LAG-3 D1-D4 domains derived from PDB 7TZG; (B) LAG-3 membrane protein is composed of D1-D4 Ig domains, D1, D2 and loop are required for the interactions with MHC-II; (C) Lymphocytes interactions via LAG-3 with MHC-II, FGL-1, LSECtin, Galectin-3, which leads to the reduced production of IL-2 and IFN-; (D) Expression of LAG-3 regulated by IL-2, IL-7 and IL-12A/B. 2. LAG-3 Expression The lymphocyte activation gene 3 (LAG-3 or CD223) is usually expressed on Natural Killer (NK) cells, invariant NK T cells, Treg cells, and both CD4+ and CD8+ subsets of T lymphocytes upon activation by antigen [11]. It was found that LAG-3 cell surface expression is usually tightly regulated by extracellular cleavage in order to regulate its potent inhibitory activity [12]. The intracellular storage of LAG-3 and its close association with the microtubule business center and recycling endosomes may facilitate its quick translocation to the cell surface during T cell activation SB225002 and help mitigate T cell activation [12]. LAG-3 is usually colocalized with CD4 in recycling endosomes, secretory lysosomes, and Rabbit Polyclonal to Histone H3 (phospho-Ser28) microtubule organizing centers which appear on the surface faster to inhibit the function of T SB225002 cells when T cells are activated [13]. The LAG-3 trafficking from lysosomal compartments to the cell surface is dependent around the cytoplasmic domain name through protein kinase C signaling in activated T cells [14]. In areas of cholesterol-rich raft aggregation LAG-3 co-localizes with CD3 and CD4/CD8 during this main response, as well as in the clustered raft region created between T cells and antibody-coated beads [15]. Furthermore, some studies confirm that LAG-3 is usually expressed also in the cytoplasm [16,17]. Lymphocyte activation gene 3 negatively regulates T cell activation, proliferation and homeostatic growth by regulatory T cell-dependent and impartial mechanisms [18]. LAG-3 expression on a subset of regulatory T cells participates in their suppressive function [18]. Study by Annunziato et al. revealed that LAG-3 is mostly expressed in Th1, conversely Th0 and Th2 clones show poor or no LAG-3 expression [19]. What is more, LAG-3 expression on activated CD4+ subsets is SB225002 usually correlated with higher.
In vivo studies showed that NK cells from LAG-3 deficient mice show defects in the killing of specific cancer cells [21]
- Post author:aftaka
- Post published:January 20, 2025
- Post category:Urotensin-II Receptor