Programmed Cell Death Protein 1 (PD1)

Programmed cell death protein 1 (PD1) is a protein that is preferentially expressed in the body’s immune B, T and NK cells. It is a transmembrane protein that binds to other proteins known as programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2), which are members of a family of co-inhibitory/co-stimulatory molecules, known as B7.

They participate in antigen presentation and are expressed by a variety of cell types. Although the molecular mechanisms of action are poorly understood, PD1 when engaged with its PD-L1/2 receptor, interferes strongly with the signal transduction of the T cell receptor (TCR). They function as a “braking system” within the immune system.

Programmed cell death 1 (PD-1, CD279, blue) immune checkpoint protein bound to programmed death-ligand 1 (PD-L1, red) protein, 3D rendering. PD-L1 is produced by tumors to suppress the immune system. Image Credit: molekuul_be / Shutterstock

PD1 consists of several parts: an extracellular binding domain that is immunoglobulin-like, a transmembrane section and a cytoplasmic domain that consists of two motifs, namely an immunoreceptor tyrosine-based switch motif (ITSM) and an immunoreceptor tyrosine-based motif (ITIM).

The ITSM and ITIM are implicated in the immunosuppressive effects of PD1. T cell functions can be enhanced by interfering with the signal transduction of PD1. This interference can be made by means, such as the use of antibody blockade, which causes potentiation of TCR signalosome signal transduction.

PD1 and T Cell Activation and Peripheral Tolerance

The immune system has an intelligent design with regards to its ability to keep self-tolerance in-check through a variety of intricate immunoregulatory networks. When T cells are called to action, their fate is determined by co-stimulatory and co-inhibitory factors regulating their activation and tolerance.

In the midst of this regulation, PD1 interacts with its PD-L1/2 ligands to send signals either directly or reversed to the cell expressing PD1 or a cell expressing its ligands, respectively.

Under normal circumstances, PD-1 induction occurs after there is activation of T cells. This then initiates an inhibitory feedback mechanism and is necessary for diminishing the signaling cascade of the TCR, thereby preventing any excessive activation of the TCR.

The resultant inhibitory response causes arrest of the cell cycle, attenuated cytokine production and a drop in the metabolism of glucose. In addition to the aforementioned intended consequences, PD1 is vital in the promotion of regulatory T-cell development and the inhibition of self-reactive T cells, which have significant potential to be pathogenic. These are both crucial roles played by PD1 in the regulation of peripheral tolerance.

Evidence that supports PD1’s role in immune regulation is illustrated in experimental models, where mice that were PD-1 deficient developed autoimmune diseases. This evidence is important to take into account with regards to the unsolicited effects that may arise when using PD1 blockade in the treatment of human disease. Nonetheless, when compared to other related B7 family members, like CTLA4, PD1 appears to play a greater role in the fight against infectious etiologies as opposed to immunological tolerance.  

Further Reading

• All Programmed Cell Death Content
• Programmed Cell Death Protein 1 (PD1) and Cancer

Written by

Dr. Damien Jonas Wilson

Dr. Damien Jonas Wilson is a medical doctor from St. Martin in the Carribean. He was awarded his Medical Degree (MD) from the University of Zagreb Teaching Hospital. His training in general medicine and surgery compliments his degree in biomolecular engineering (BASc.Eng.) from Utrecht, the Netherlands. During this degree, he completed a dissertation in the field of oncology at the Harvard Medical School/ Massachusetts General Hospital. Dr. Wilson currently works in the UK as a medical practitioner.