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PD-1 Suppresses T Cell Activation

Binding of PD-L1 or PD-L2 to PD-1 Inhibits T Cell Activation

PD-1 is a second T cell co-inhibitory receptor belonging to the CD28 family whose expression is induced on T cells following TCR stimulation or in the presence of specific cytokines. PD-1 binds to two ligands, PD-L1/B7-H1 and PD-L2/B7-DC, which are expressed on antigen-presenting cells and up-regulated in response to IFN-gamma.1 Binding of PD-1 to either PD-L1 or PD-L2 interferes with early TCR/CD28 signaling and inhibits IL-2 production and T cell proliferation, T cell effector functions, and T cell survival. 2-4 Tumor cells frequently up-regulate PD-L1, allowing them to suppress anti-tumor T cell responses and evade immune system destruction through PD-1. 2, 4-6 Similar to CTLA-4, up-regulated expression of PD-1 is also associated with T cell exhaustion in cancer, and blocking the functions of PD-1 or PD-L1 with antagonistic monoclonal antibodies has been shown to boost the anti-tumor immune response in many different types of human cancer. 4, 7, 8

PD-L1 and PD-L2 Provide Secondary Signals that Inhibit T Cell Activity

The interaction between PD-L1 or PD-L2 and the T cell receptor, PD-1, inhibits T cell activation.

Binding of PD-L1 or PD-L2 to PD-1 delivers a T cell co-inhibitory signal. Following TCR activation, expression of the co-inhibitory receptor, PD-1, is induced on naïve T cells. Ligation of PD-1 by either of its ligands, PD-L1/B7-H1 or PD-L2/B7-DC, expressed on antigen-presenting cells (APCs) inhibits TCR-mediated T cell proliferation and cytokine production. In cancer, PD-L1 is frequently expressed by tumor cells and other cells present in the tumor microenvironment including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). PD-L1 expressed on tumor cells, TAMs, or MDSCs binds to T cell-expressed PD-1 and suppresses T cell-mediated anti-tumor immune responses. Up- regulated expression of PD-1 is also found on exhausted T cells in cancer and is thought to contribute to T cell dysfunction.

Analysis of the Binding Properties of R&D Systems PD-L1:PD-1 Proteins by SPR

Surface plasmon resonance data showing the affinity measurements and binding kinetics between the PD-L1 and PD-1 proteins.

Affinity Measurements and Binding Kinetics of the PD-1:PD-L1 Interaction by Surface Plasmon Resonance. Sensorgram data of captured Avi-tag Biotinylated Recombinant Human PD-L1 His tag (R&D Systems, Catalog # AVI9049) binding to Recombinant Human PD-1 His tag (R&D Systems, Catalog # 8986-PD). The corresponding overlaid kinetic fits with the residual plot shown below. The concentration of Recombinant Human PD-1 His-tag ranged from 3.2 nM to 13.2 μM. The corresponding steady state affinity fit is shown below. The experiment was performed on a BiacoreT200, GE Healthcare.

Analysis of the Purity of R&D Systems PD-L1 Protein using CE-SDS on the Maurice System

Purity of Recombinant Human PD-L1/B7-H1 assessed by CE-SDS on Maurice under reducing (R) and non-reducing (NR) conditions and visualized in Compass for iCE software.

Assessment of the Purity of Recombinant Human PD-L1/B7-H1 by CE-SDS on the MauriceTM System. The purity of Recombinant Human PD-L1/B7-H1 Fc Chimera (R&D Systems, Catalog # 156-B7) was assessed by capillary electrophoresis (CE)-SDS on the Maurice System under reducing (R) and non-reducing (NR) conditions and visualized in Compass for iCE software. The gel view is shown as an inset with the relative migration time (RMT) on the electropherogram shown on the far right-hand side of the gel.

References

2. Wang, Y. et al (2018) Regulation of PD-L1: Emerging routes for targeting tumor immune evasion. Front. Pharmacol. 9 536 PMID: 29910728

3. Schildberg, F.A. (2016) Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44 955 PMID: 27192563

4. Seidel, J.A. et al (2018) Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front. Oncol. 8 86 PMID: 29644214

5. Topalian, S.L. et al (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27 450 PMID: 25858804

6. Zheng, Y. et al (2019) PD-L1 expression levels on tumor cells affect their immunosuppressive activity. Oncol. Lett. 18 5399 PMID: 31612048

7. Wherry, E.J. & M. Kurachi (2015) Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15 486 PMID: 26205583