Regulation of expression of the human lymphocyte activation gene-3 ( LAG-3 ) molecule, a ligand for MHC class II

Abstract

The lymphocyte activation gene-3 (LAG-3), a major histocompatibility complex (MHC) class II ligand evolutionarily related to CD4, is expressed exclusively in activated T and NK lymphocytes and seems to play a role in regulating the evolving immune response. We first determined that surface LAG-3 expression on activated human T cells is upregulated by certain cytokines (IL-2, IL-7, IL-12) and not by others (IL-4, IL-6, IL-10, TNF-alpha, TNF-beta, IFN-gamma). Surface LAG-3 expression correlated with intracellular IFN-gamma production in both CD4+ and CD8+ T-cell subsets. We then analyzed the 5' transcription control sequences of LAG-3. A DNase I hypersensitive site induced in T cells following cellular activation was found in the region including the transcriptional start site, showing that DNA accessibility is a mechanism which restricts LAG-3 expression to activated T cells. Transcription is initiated at three sites. A GC box, 80 base pairs (bp) upstream of the major transcription start site, forms a minimal promoter which is regulated by two upstream regions containing positive and negative regulatory elements with multiple protein binding sites as shown by footprinting analysis. In particular, a GATA/c-Ets motive was identified in a short segment homologous to the mouse CD4 distal enhancer, suggesting that LAG-3, which is embedded in the CD4 locus, may be controlled by some CD4 regulatory elements. Finally, a 100 bp region downstream of the transcription start site was shown to be involved in the cell-specific control of LAG-3 expression. Understanding this highly regulated expression may help to determine the intriguing role of this activation-induced MHC class II ligand.

Sequencing-based approach identified three new susceptibility loci for psoriasis

“…LAG3, a ligand for MHC class II receptors, is closely related to CD4 and downregulates the activated T-cells on which it is expressed through a high-affinity interaction with its receptor; this interaction blocks the binding of CD4 (ref. 24). Studies in LAG3 knockout mice have shown that LAG3 negatively regulates both the expansion of T-cells and the size of the memory-T-cell pool 25 .…”

Lymphocyte Activation Gene-3 Expression Defines a Discrete Subset of HIV-Specific CD8+T Cells That Is Associated with Lower Viral Load

“…Surface LAG-3 expression on activated human T cells is upregulated by interleukin IL-2, IL-7, and IL-12 and thus may play an essential role during activation. 41 LAG-3 has been associated as an inhibitory marker and in immune suppression. 3,8,9,11,15,16,42,43 Given the similarities in downstream targets, it is tempting to speculate that inhibitory molecules may act antagonistically against other positive costimulation.…”

High Expression of Lymphocyte-Activation Gene 3 (LAG3) in Chronic Lymphocytic Leukemia Cells Is Associated with Unmutated Immunoglobulin Variable Heavy Chain Region (IGHV) Gene and Reduced Treatment-Free Survival

“…LAG3 (CD223) was identified in 1990 by authors Triebel et al This surface protein is related to CD4 molecule and physiologically expressed on T-cells and natural killer-cells after cell activation and not on resting peripheral blood lymphocytes. 31 Surface LAG3 expression on activated human T-cells is up-regulated by interleukin IL-2, IL-7, and IL-12, 32 and is detectable on all human T-cells 2 to 3 days after activation. 33 Therefore LAG3 probably does not take part in induction phase of immune response but may play essential role during activation.…”