LAG-3 Negatively Regulates T Cell Functions

LAG-3 Interacts with Multiple Ligands and Inhibits T cell Responses

Lymphocyte Activation Gene 3 (LAG-3), also known as CD223, is a type I transmembrane protein that belongs to the immunoglobulin superfamily (IgSF). It is expressed as a dimer or as an oligomer on the surface of activated CD4⁺ and CD8⁺ T cells, regulatory T cells, Tr1 cells, natural killer cells, and plasmacytoid dendritic cells (pDCs).^{1, 2} Similar to PD-1 and CTLA-4, LAG-3 is also up-regulated on exhausted T cells in cancer.^2,3 The LAG-3 protein is structurally homologous to CD4 in that it has four extracellular Ig-like domains, but it also contains an extra loop on the membrane-distal Ig-like domain that is not present in CD4. This extra loop allows the LAG-3 protein to bind to MHC class II molecules expressed on antigen-presenting cells (APCs) or tumor cells with significantly higher affinity than CD4, and negatively regulate T cell receptor (TCR) signaling.^{4, 5}

In addition to MHC class II molecules, Galectin-3, LSECtin, and Fibrinogen-like protein 1 (FGL1) are also LAG-3 ligands.^{2, 6-8} Significantly, all three of these proteins are expressed on various tumor cell types and inhibit T cell responses, making it unclear which ligands are primarily responsible for the immunosuppressive functions of LAG-3.^{6, 8} Although the mechanisms by which LAG-3 signals are not well understood, LAG-3 has been shown to negatively regulate T cell activation, proliferation, and cytokine production, inhibit pDC activation, and enhance the suppressive activity of regulatory T cells.^9-15 LAG-3 has also recently been suggested to inhibit cytokine secretion by mature natural killer cells.¹⁶ On regulatory T cells, LAG-3 was found to engage MHC class II on dendritic cells (DCs) and inhibit DC maturation and their immunostimulatory capacity .¹⁷ Conversely, a soluble variant of LAG- 3 was shown to bind to MHC class II molecules on immature DCs and induce their maturation, leading to enhanced CD8⁺ T cell antigen cross-presentation.^{18, 19}

Similar to PD-1, LAG-3 is frequently up-regulated on tumor-infiltrating lymphocytes (TILs) and while blockade of LAG-3 alone was found to be only weakly effective in reducing tumor growth in some mouse tumor models, blockade of both LAG-3 and PD-1 synergistically enhanced anti-tumor immunity and survival, when compared with anti-PD-1 alone.^{20, 21} In many of these mouse tumor models, the improvement in the anti-tumor immune response was attributed to an increase in the number of tumor-infiltrating CD8⁺, or CD8⁺ and CD4⁺ T cells, and an accompanying increase in IFN-gamma production that was observed following anti-LAG-3/anti-PD-1 treatment. As a result, researchers are now evaluating an antagonistic anti-LAG-3 antibody either alone, or in combination with anti-PD-1, in clinical trials.^{22, 23} Additionally, due to the observation that soluble LAG-3 has immune-stimulatory effects, a soluble recombinant form of LAG-3, known as IMP321, is also being evaluated in phase I testing in combination with anti-PD-1.

Bio-Techne offers R&D Systems^TM bioactive recombinant proteins for LAG-3 and its ligands, along with fluorochrome-conjugated antibodies for detecting LAG-3, Galectin-3, and LSECtin to further our understanding of the immunomodulatory effects of LAG-3.

LAG-3 and LAG-3 Ligands - Products by Molecule

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