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LAG-3 (approved gene symbol) is closely related to CD4 at the gene and protein levels (Triebel et al, 1990). In the nomenclature of CD antigens this protein has been given the designation CD223.

This protein has been identified as an antigen expressed on T-cells and NK-cells after cell activation. It is not expressed on resting peripheral blood lymphocytes (Triebel et al, 1990). Workman et al (2002) have reported that very few (<3 %) Alpha-Beta T-cells (memory T-cells) in the spleen and thymus of naive mice express surface CD223. Approximately 18 % Gamma-Delta T-cells and approximately 10 % NK-cells express the antigen. All T-cells express CD223 2-3 days after cell activation. Scala et al (1998) have reported that most CD8(+) clones producing IL4 but not IFN-gamma (i.e., with a Th2 like profile) also express LAG-3 and frequently also express CD30.

Surface LAG-3 expression on activated human T-cells is upregulated by IL2, IL7, IL12, but not by IL4, IL6, IL10, TNF-alpha, TNF-beta, IFN-gamma, and correlates with intracellular IFN-gamma production in both CD4(+) and CD8(+) T-cell subsets (Bruniquel et al, 1998).

Kisielow et al (2005) have reported that LAG-3 is expressed also on activated B-cells. B-cell surface expression depends on the presence of T-cells and is mediated by a soluble factor. B-cells do not express LAG-3 when activated by Toll-like receptor agonists alone and thus may serve as a marker for T-cell induced B-cell activation.

Li et al (2004) have shown that LAG-3 is cleaved into two fragments, which may influence its functions. A 54 kDa fragment comprising the extracellular domain oligomerizes with full-length LAG-3 (70 kDa) on the cell surface. A 16 kDa peptide with the transmembrane and cytoplasmic domains is created also. The 54 kDa fragment is released as soluble LAG-3 (sLAG-3). T-cell activation increases the release of sLAG-3 and its appearance in the sera of C57BL/6 and RAG-1(-/-) mice.

LAG-3 is a multifunctional protein affecting different cell types. Baixeras et al (1992) have reported that LAG-3 protein is a ligand for human leukocyte antigen class 2 antigens. MHC class 2 engagement by LAG-3 affects the migration of dendritic cells to secondary lymphoid tissues. LAG-3 engagement induces production of IL8, CCL3 (MIP-1-alpha), CCL22 (MDC), and CCL17 (TARC) in dendritic cells. These cells downregulate surface expression of the CCL3 receptor CCR5 and upregulate CCR7 (a receptor for MIP-3-beta and SLC). LAG-3-matured dendritic cells retain their capacity to respond to MIP-1-alpha (Buisson and Triebel, 2003). LAG-3 signaling has been shown to inhibit early events in primary activation of human CD4(+) and CD8(+) T-cells (Macon-Lemaitre and Triebel, 2005).

The interaction of LAG-3 with class 2 molecules controls CD4(+) T-cell responses and leads to the downregulation of CD4(+) antigen-specific T-cell clone proliferation and cytokine secretion (Huard et al, 1996). LAG-3 expression by activated antigen-stimulated CD4(+) human T-cells leads to the production of IFN-gamma (Annunziato et al, 1996).

LAG-3 has been shown to play a role in regulating the expansion of activated T-cells (Workman and Vignali, 2003) and to control the size of the memory T-cell pool (Workman et al, 2004). Huang et al (2004) have reported that LAG-3 is required for maximal regulatory T-cell function. LAG-3 is expressed by regulatory T-cells and that antibodies to LAG-3 inhibit suppression by induced Tregs both in vitro and in vivo. Regualtory T-cells from LAG-3 knock-out mice show reduced regulatory activity. Workman et al (2002) have analysed the negative regulatory function of LAG-3, demonstrating that it inhibits CD4 dependent, but not CD4 independent, T-cell function via its cytoplasmic domain.

Andreae et al (2002) have reported that LAG-3 as the natural ligand for MHC class 2 causes complete maturation of dendritic cells, as demonstrated by the production of IL12 and TNF-alpha by these cells and increases in the capacity of dendritic cells to stimulate the proliferation and IFN-gamma response by allogeneic T-cells.

Avice et al (1999) have reported that LAG-3 activation stimulates production of TNF-alpha and IL12 by monocytes and dendritic cells cocultured with T-cells.

Hannier et al (1998) have reported that LAG-3 can downregulate the immune response by interfering with signaling through T-cell receptor and CD3 complexes.

Huang et al (2004) have reported that ectopic expression of LAG-3 on CD4(+) T-cells significantly reduces their proliferative capacity and confers on them suppressor activity toward effector T-cells. Workman and Vignali (2005) have reported that LAG-3 negatively regulates T-cell homeostasis and also affects the expansion of B-cells, macrophages, granulocytes, and dendritic cells.

Buisson and Triebel (2005) have reported that LAG-3 reduces macrophage and dendritic cell differentiation from monocyte precursors.

Triebel et al (2006) have reported that high levels of soluble LAG-3 protein (sLAG-3) in sera of human breast cancer patients correlate with disease-free intervals after first diagnosis and overall survival rates in patients with estrogen or progesterone receptor positive tumor cells. Carlo et al (2005) have reported that LAG-3 expression by engineered tumor cells efficiently promotes intra-tumoral recruitment, activation, and Th1 commitment of antibody-presenting cells (dendritic cells, macrophages) and leads to a wide intra-tumoral influx of non-specific and specific reactive cells (granulocytes, NK-cells, CD4(+) T-cells, CD8(+) IFN-gamma expressing cells), and the release of immunoregulatory and cytotoxic mediators by infiltrating leukocytes (IFN-gamma, TNF-alpha, IL1-beta, CXCL5, CXCL9, CXCL10, CXCL11, CCL5, CCL2).

Miyazaki et al (1996) have reported that knock-out mice lacking expression of LAG-3 exhibit NK-cell defects rather than T-cell defects. Killing of some tumor target cells by NK-cells from these mice is inhibited or even abolished, whereas MHC complex class 1-dependent cell lysis remains unaffected.

For additional information on CD antigens see also: CD antigens MiniCOPE Dictionary.

Copyright 2012 by H IBELGAUFTS. All rights reserved.


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