Ligands for Common Immune Checkpoints

Immune checkpoints and their corresponding ligands play a pivotal role in shaping the immune response and influencing the outcome of immune-related diseases, including cancer. Although immune checkpoints are key regulators, their functions are intricately intertwined with ligands. Therefore, an in-depth understanding of these immune checkpoint ligands is necessary.

At Creative Biolabs, we are committed to unraveling the mysteries surrounding immune checkpoints and developing innovative solutions.

Multiple immune checkpoint receptor-ligand interactions between T cells and APCs or tumor cells.Fig. 1 Multiple immune checkpoint receptor-ligand interactions between T cells and APCs or tumor cells. (Moon J, et al., 2021)

Ligands of PD-1

PD-1-mediated T-cell suppression can be attributed to two well-known ligands of PD-1, namely PD-L1 and PD-L2 (B7-DC, CD273).

  • PD-L1 is the more dominant ligand of PD-1 compared to PD-L2. PD-L1 expression in tumor cells usually occurs during malignant transformation. PD-L1 expressed by tumor-infiltrating immune cells promotes immune escape through multiple mechanisms.
  • As a second ligand for PD-1, PD-L2 also confers PD-1 inhibitory function, although the mechanism is not fully understood. PD-L2 binds PD-1 with higher affinity than PD-L1, and PD-L2 expression was initially thought to be restricted to dendritic cells or macrophages, but recent studies have shown that its expression in many human malignancies.

Ligands for TIGIT

TIGIT is a suppressor receptor expressed mainly by NK cells, regulatory T cells, memory T cells and depleted CD8+ T cells. Human TIGIT binds to three ligands, including

  • Poliovirus receptor (PVR, NECL5, CD155)
  • PVR-related 2 (PVRL2, NECIN2, CD112)
  • PVR-related 3 (PVRL3, NECIN3, CD113)

PVR has the highest affinity for TIGIT. PVR/TIGIT binding inhibits T cell responses by phosphorylating the immunoreceptor tyrosine-based inhibitory motif (ITIM) in the intracellular segment of TIGIT or by interfering with PVR/DNAX-related molecule 1 (DNAM-1, CD226) binding.

Ligands of TIM-3

TIM-3, a marker of T cell depletion, is one of the most common targets in immunotherapy. TIM-3 has four ligands:

  • Galactose lectin-9 (Gal-9)
  • Phosphatidylserine (PtdSer)
  • High mobility group protein box 1 (HMGB1)
  • Carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1)

Among them, Gal-9 and CEACAM1 attenuate TCR signaling by isolating HLAB-associated transcript 3 (BAT3) from TIM-3, and ultimately lead to apoptosis. Furthermore, intracellular interactions between TIM-3 and CEACAM1 support the maturation and surface transport of TIM-3. To date, interactions between TIM-3 and PtdSer or HMGB1 are known to indirectly affect T cell function, but whether PtdSer or HMGB1 directly affects TIM-3 expressing T cells remains to be investigated.

Ligands of LAG-3

Five LAG-3 ligands have been identified so far:

  • MHC II
  • Galactose lectin-3 (Gal-3)
  • Liver sinusoidal endothelial cell lectin (LSECtin)
  • α-synucleinogenic fibrils (α-syn)
  • Fibrinogen-like protein 1 (FGL1)

It was found that APCs that abundantly express pMHCII inhibit CD8+ T cell activation through a LAG-3-dependent mechanism. In addition, other ligands including Gal-3, LSECtin and FGL1 bound to LAG-3 can negatively regulate CD8+ T cells in the tumor microenvironment.

Intra-tumor CD8+ T cells and stromal cells are the main sources of Gal-3, but Gal-3 can also be secreted by many types of tumor cells. LSECtin or FGL1 is expressed in the liver under normal physiological conditions and is highly upregulated in some tumor cells. Future studies are needed to verify the precise molecular mechanisms of these ligands and their role in LAG-3-mediated T-cell suppression.

Ligands for VISTA

One study identified VSIG3 (or IgSF11) as a VISTA ligand, and this interaction contributes to the suppression of T-cell responses. Since VSIG3 expression in hematopoietic cells is undetectable, the physiological relevance of this interaction in vivo remains to be verified. In addition, a pH-dependent interaction between VISTA and P-selectin glycoprotein ligand-1 (PSGL-1) has been found.

In conclusion, the exploration of ligands for common immune checkpoints has provided us with valuable insights into the delicate balance between immune activation and inhibition. With further advancements in our understanding of these intricate mechanisms, we can anticipate the development of innovative immunotherapeutic approaches.


  1. Moon J, et al. Perspectives on immune checkpoint ligands: expression, regulation, and clinical implications. BMB reports, 2021, 54(8): 403.

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