Programmed Cell Death Protein 1 (PD1)

Programmed cell death protein 1 (PD-1) is a protein that is preferentially expressed in the body’s immune B, T, and natural killer (NK) cells. PD-1 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.

Taken together, PD-L1 and PD-L2 participate in antigen presentation and are expressed by a variety of cell types. Although the molecular mechanisms of action are poorly understood, PD-1, when engaged with its PD-L1/2 receptor, interferes strongly with the signal transduction of the T cell receptor (TCR). As a result, these proteins function as a “braking system” within the immune system.

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PD-1 consists of several parts which include 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).

Both ITSM and ITIM are implicated in the immunosuppressive effects of PD-1. T cell functions can be enhanced by interfering with the signal transduction of PD-1. This interference can be made by several different mechanisms, such as the use of antibody blockade, which causes potentiation of TCR signalosome signal transduction.

PD-1 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, PD-1 interacts with its PD-L1/2 ligands to send signals either directly or reversed to the cell expressing PD-1 or a cell expressing its ligands, respectively.

Under normal circumstances, PD-1 induction occurs after there is an 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, PD-1 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 PD-1 in the regulation of peripheral tolerance.

Evidence that supports PD-1’s role in immune regulation is illustrated in experimental mouse models 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 PD-1 blockade in the treatment of human disease. Nonetheless, when compared to other related B7 family members, like CTLA4, PD-1 appears to play a greater role in the fight against infectious etiologies as opposed to immunological tolerance.  

References

Further Reading

Last Updated: May 12, 2021

Dr. Damien Jonas Wilson

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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.

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