PDCD1

What is PDCD1 protein?

PDCD1 (programmed cell death 1) gene is a protein coding gene which situated on the long arm of chromosome 2 at locus 2q37. PDCD1 is an immunosuppressive receptor expressed in activated T cells. PDCD1 is a member of the immunoglobulin superfamily and plays an important role in T cell inhibitory signaling. By binding to two ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), it is involved in regulating the function of T cells, in particular playing a key role in inducing and maintaining immune tolerance to itself. Structurally, PDCD1 protein is located in the plasma membrane of the cell and has a variety of post-translational modifications, including phosphorylation, ubiquitination, and n-glycosylation. The expression of PDCD1 is mainly on T cells and pre-B cells, especially after T cell activation, its expression level will increase. The PDCD1 protein is consisted of 288 amino acids and its molecular mass is approximately 31.6 kDa.

What is the function of PDCD1 protein?

The PDCD1 protein, also known as PD-1, is an important immunomodulatory molecule that is mainly expressed in the T cells of the immune system. The biological function of PD-1 protein mainly involves the following aspects:

Immune tolerance and autoimmune regulation. By interacting with its two ligands, PD-L1 and PD-L2, PD-1 regulates the activity of T cells, particularly playing a role in maintaining immune tolerance and preventing autoimmune reactions. When T cells are activated, the expression of PD-1 increases and, by binding to PD-L1 and PD-L2, inhibits the proliferation of T cells and the production of cytokines, thereby limiting the occurrence of autoimmune responses.

Anti-tumor immune response. In the tumor microenvironment, PD-1 binds to PD-L1 on the surface of tumor cells and inhibits the function of tumor-infiltrating T cells, leading to dysfunction and failure of T cells, thereby helping tumor cells evade the surveillance and attack of the immune system.

B cell function regulation. PD-1 also plays a role in the differentiation and maturation of B cells, influencing humoral immune responses by regulating B cell activation and antibody production.

PDCD1 Related Signaling Pathway

The PDCD1 protein is a membrane protein mainly expressed on immune cells, which plays a key role in regulating the activation and tolerance of the immune system. By binding to its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC), PD-1 mainly participates in the following signaling pathways: T cell receptor (TCR) signaling pathway, PD-1 signaling can inhibit PI3K/Akt pathway, which is an important signaling pathway for promoting cell survival and metabolism. In T cells, this inhibition leads to functional failure and depletion. mTOR signaling pathway, NF-κB signaling pathway and JAK/STAT signaling pathway.

Fig1. Mechanisms of PD-1/PD-L1 pathway in T cells. (Xiaowei Liu, 2023)

PDCD1 Related Diseases

Tumors. The role of the PD-1/PD-L1 signaling pathway in a variety of tumors has been extensively studied, particularly in tumor immune escape. By expressing PD-L1 and binding to PD-1 on T cells, tumor cells inhibit the T-cell-mediated immune response, thereby promoting tumor growth and metastasis.

Autoimmune disease. PD-1 also plays an important role in autoimmune diseases. For example, in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), the expression level of PD-1 correlates with the severity of the disease.

Lentiviral infections, immune-related inflammatory diseases, and autoimmune eye diseases are also associated with the PD-1/PD-L1 signaling pathway.

Bioapplications of PDCD1

The application of PD-1 protein in the field of tumor therapy is the most extensive and the most in-depth. PD-1 inhibitors, including anti-PD-1 antibodies and anti-PD-L1 antibodies, can block the binding of PD-1 to its ligand, relieve the inhibition of tumor cells on T cells, so as to restore and enhance the ability of T cells to attack tumors. These inhibitors have become an important part of the treatment of many cancers, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and head and neck squamous cell carcinoma (HNSCC).

Case Study 1: Christina Martins, 2024

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, the researchers identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis.

Fig1. Representative flow cytometric analysis of PD-1 surface protein.

Fig2. Tumor growth kinetics (means ± SEM) of MKL-2 or WaGa cells grafted to NSG mice.

Case Study 2: Tao Jiang, 2024

Apoptosis triggers immunoregulation to prevent and suppress inflammation and autoimmunity. However, the mechanism by which apoptotic cells modulate immune responses remains largely elusive. In the context of allogeneic mesenchymal stem cells (MSCs) transplantation, long-term immunoregulation is observed in the host despite the short survive of the injected MSCs. In this study, utilizing a mouse model of acute lung injury (ALI), the researchers demonstrate that apoptotic bodies (ABs) released by transplanted human umbilical cord MSCs (UC-MSCs) convert the macrophages from a pro-inflammatory to an anti-inflammatory state, thereby ameliorating the disease. Mechanistically, they identify the expression of programmed cell death 1 ligand 1 (PDL1) on the membrane of UC-MSCs-derived ABs, which interacts with programmed cell death protein 1 (PD1) on host macrophages. This interaction leads to the reprogramming of macrophage metabolism, shifting from glycolysis to mitochondrial oxidative phosphorylation via the Erk-dependent pathway in ALI. Importantly, we have reproduced the PDL1-PD1 effects of ABs on metabolic switch using alveolar macrophages from patients with ALI.

Fig3. The expressions of PD1 and PDL1 were assessed by western blot analysis.

Fig4. Line graph showing extra-cellular acidification rate (ECAR) from seahorse analysis assessed in BMDMs.

PDCD1 has several biochemical functions, for example, protein binding,signal transducer activity. Some of the functions are cooperated with other proteins, some of the functions could acted by PDCD1 itself. We selected most functions PDCD1 had, and list some proteins which have the same functions with PDCD1. You can find most of the proteins on our site.

PDCD1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with PDCD1 here. Most of them are supplied by our site. Hope this information will be useful for your research of PDCD1.

CD274;PTPN6;PTPN11;AGO1