TL1A Immune Checkpoint Molecule for Drug Development

Introduction to TL1A

TNF-like ligand 1A (TL1A), also known as TNFSF15, is a member of the tumor necrosis factor (TNF) family that plays a significant role in regulating IFN-gamma (IFN-γ) production. It can be found in many cell types, such as natural killer cells (NKs), antigen presentation cells (APCs), and endothelial cells. Pilot studies have demonstrated that TL1A can bind with the death domain-containing receptor (DR3) and the decoy receptor (DcR3) to exert multiplex activities on T cell proliferation, activation, as well as differentiation. Moreover, recent reports have revealed that TL1A and DR3 expression are up-regulated in a wide variety of autoimmune and inflammatory diseases, like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Knockout studies in mice have also indicated that the blocking of TL1A-DR3 interaction can reduce IBD severity. As a result, TL1A/DR3 should be potential therapeutic targets for drug development.

Checkpoint molecule Alternate name Cell type affected Surface receptor The function of ligand-receptor interaction
TL1A TNFSF15 T cells, monocytes, macrophages, dendritic cells (DCs), synovial fibroblasts, and endothelial cells DR3 (TNFSF25, WSL-1, TRAMP, LARD) and DcR3 Co-stimulatory

The Structure of TL1A

Currently, the structure of human TL1A has been identified by X-ray crystal diffraction. In general, it has a similar structure to the TNF family, with two β-sheets. The inner β-sheet of TL1A is made up of the A' AHCF strand, and the outer β-sheet of TL1A is composed of the B' AHCF strand. Typically, the AA', CD, and EF loop segments of TL1A are different from the TNF family. The AA' and CD loop segment are longer than most TNF ligands, whereas the EF loop segment is much shorter. Moreover, sequence analysis has suggested that TL1A has a 2.02 kb length of open reading frame that encodes approximately 250 amino acids. It also contains a C-terminal signal peptide domain, a transmembrane domain, as well as a carboxyl domain that shares 20%-60% sequence homology to other TNF superfamily members, like FasL.

Ribbon structure of TL1A trimer assembly. Fig.1 Ribbon structure of TL1A trimer assembly. (Zhan, 2009)

TL1A Immune Checkpoint Molecule for Drug Development

TL1A, a ligand of DR3 and DcR, has been regarded as a new immune checkpoint molecule and a potential target for disease treatment. Up to now, many studies have illustrated that TL1A/DR3 system is essential to mediate various immune responses and may participate in the discovery of novel drugs. Meanwhile, TL1A/DR3 immune checkpoint can trigger immune responses by two distinct signaling cascades, mitogen-activated protein kinases (MAPK) signaling pathway and NF-κB signaling pathway. In particular, TL1A/DR3 signaling can enhance Th1 effector response, increase the response of TCR-stimulated T cells to specific cytokines, such as INF-γ, IL-2, and IL-15, and modulate the proliferation and function of regulatory T cells.

Consequently, many organizations and companies have been focused on providing immune checkpoint TL1A-based drug discovery and development services for the treatment of different diseases. Different drugs, including but not limited to antibodies, and small-molecule drugs, have been generated and broadly evaluated by both pre-clinical and clinical trials. Please do not hesitate to contact us for more detailed information.


  1. Zhan, C.; et al. Biochemical and structural characterization of the human TL1A ectodomain. Biochemistry. 2009, 48(32): 7636-7645.

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