PD-1

Programmed Death1 (PD1) is a type I transmembrane protein belonging to the CD28/CTLA4 family of immunoreceptors that mediate signals for regulating immune responses. Members of the CD28/CTLA4 family have been shown to either promote T cell activation (CD28 and ICOS) or downregulate T cell activation (CTLA4 and PD1) . PD1 is expressed on activated T cells, B cells, myeloid cells, and on a subset of thymocytes. In vitro, ligation of PD1 inhibits TCRmediated T cell proliferation and production of IL1, IL4, IL10, and IFNγ. In addition, PD1 ligation also inhibits BCR mediated signaling. PD1 deficient mice have a defect in peripheral tolerance and spontaneously develop autoimmune diseases. Two B7 family proteins, PDL1 (also called B7H1) and PDL2 (also known as B7DC), have been identified as PD1 ligands. Unlike other B7 family proteins, both PDL1 and PDL2 are expressed in a wide variety of normal tissues including heart, placenta, and activated spleens. The wide expression of PDL1 and PDL2 and the inhibitor effects on PD1 ligation indicate that PD1 might be involved in the regulation of peripheral tolerance and may help prevent autoimmune diseases. The human PD1 gene encodes a 288 amino acid (aa) protein with a putative 20 aa signal peptide, a 148 aa extracellular region with one immuno-globulin-like V-type domain, a 24 aa transmembrane domain, and a 95 aa cytoplasmic region. The cytoplasmic tail contains two tyrosine residues that form the immunoreceptor tyrosinebased inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM) that are important in mediating PD1 signaling. Mouse and human PD1 share approximately 60% aa sequence identity.