Programmed cell death protein 1, Protein PD-1, hPD-1, CD279, PDCD1
Activated T cells express the programmed cell death protein 1 (PD-1), which belongs to the CD28 family of the immunoglobulin superfamily. As immune checkpoint receptor, PD-1 represents a key player in modulating adaptive immune responses to prevent both excessive stimulation of the immune system and tissue damage. It interacts with two ligands, PD-L1 and PD-L2. PD-L1 is expressed on antigen-presenting cells (APCs) and many other tissue cells, whereas PD-L2 is mainly expressed on APCs. Structurally, PD-1 consists of an extracellular immunoglobulin domain, a transmembrane domain, and a cytoplasmic tail. The cytoplasmic tail contains two tyrosine-based signaling motifs, referred to as immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). Engagement of PD-1 with its ligands results in the recruitment of phosphatases to these signaling motifs und induces inhibitory signals that suppress T cell activation. In contrast to CTLA-4, PD-1 is not a competitive inhibitor, but inhibits kinase-dependent signals from CD28 and T cell receptor (TCR) upon ligand engagement. Moreover, PD-1 rather limits the responses of effector T cells, predominantly CD8+ T cells, in peripheral tissues. This regulatory function is essential for preventing autoimmunity and maintaining immune tolerance. Cancer cells often upregulate the expression of PD-L1, enabling interaction with PD-1 on infiltrating T cells and thus, inducing immune tolerance within the tumor microenvironment. This immune evasion strategy allows cancer cells to escape destruction by the immune system, promoting tumor growth and progression. Immune checkpoint inhibitors, such as monoclonal antibodies targeting PD-1, have demonstrated remarkable clinical efficacy in various cancer types by unleashing the anti-tumor immune response.
