DR3 and TL1A Pathway

Introduction to DR3 and TL1A Pathway

Tumor necrosis factor (TNF)-like molecule 1a (TL1A, also called TNFSF15 and VEGI-251) is a new member of the TNF cytokine superfamily that plays an important role in regulating the production of IFN-γ. The TL1A is a longer variant of the protein TL1 (also named vascular endothelial growth inhibitor, VEGI) encoded by the TNFSF15 gene. Its formula weight is 28-kDa and contains 251 amino acids. Like other TNF family members, TL1A is a type II transmembrane protein that self-assembles into a homo-trimer. It comes in a membrane-bound and a soluble form, where the soluble form protein about 20-kDa named sTL1A, is cleaved from the surface by ectodomain shedding. The sTL1A is functionally identical to the membrane-bound form of TL1A (mTL1A). The expression of the TL1A gene can be found in many types of cells, such as antigen presentation cells (APCs), lymphocytes, vascular endothelial cells (ECs), natural killer cells (NKs), and even plasma cells.

Death receptor 3 (DR3, also known as LARD, TRAMP, Wsl-1, Apo3, TNFRSF25, and TR3), is one of the family members of death receptors that constitute a subgroup of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) and have been functionally linked to two cell death modalities: apoptosis and necroptosis. DR3 is a 45-kDa protein and comprised of 417 amino acids, it has a functional structure in its cytoplasmic region named death domain (DD). DR3 is the primary activating receptor of TL1A and it is mainly expressed on leukocytes. It has especially been characterized on subsets of activated lymphocytes, primarily those with more innate-like effector functions, such as IECs and the recently defined T-cell lineage, tissue-resident memory (Trm) T cells, and cytokine-activated T cells. DR3 is a very powerful lymphocyte costimulator, and its signaling amplifies various effecter functions for the induction of both T-cell proliferation and secretion of proinflammatory cytokines.

Research of DR3 and TL1A Pathway

The DR3 and TL1A pathway is associated with two distinct downstream NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and caspase signaling pathways. The former pathway being pro-inflammatory results in cytokine secretion, cell proliferation, and cell activation through the ability of the DD of DR3 which can bind to the TNFR-associated death domain protein (TRADD), and then stimulate the mitogen-activated protein kinases (MAPK) and following the NF-κB activation. The second cascade is associated with the activation of the effector caspases such as caspase 3, and after a series of morphological changes like membrane blebbing, cell shrinkage, and nuclear fragmentation, ultimately leads to cell apoptosis.

Fig1. DR3 and TL1A pathway regulation and function.¹

The synergistic effect of TL1A on immune cell activation has shown significant potential in recent studies of human diseases such as rheumatoid arthritis (RA), psoriasis, and primary biliary cirrhosis (PBC). The synergistic signaling of DR3 together with members of the IL-1 and Toll-like receptor superfamily has been proven to produce very potent secretory cytokine responses in both monocyte-derived APCs and T cells. Besides, TL1A is increasingly being recognized as an innate inducer of chronic inflammation. Furthermore, TL1A can synergize with the cytokines IL-12 and IL-18, resulting in a powerful TCR-independent cytokine secretion.

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Reference

1. Siakavellas, et al. "Tumor necrosis factor–like cytokine TL1A and its receptors DR3 and DcR3: important new factors in mucosal homeostasis and inflammation." Inflammatory bowel diseases 21.10 (2015): 2441-2452.

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