4.1.1　Structure and Expression of PD-1

Programmed death-1 (PD-1) is a 50-55 kDa type I trans membrane glycoprotein composed of an IgV-type extracellular domain sharing 21%-33% sequence identity with cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), CD28 and inducible co-stimulatory molecule (ICOS).Unlike CTLA-4 that forms homodimer, PD-1 lacks the membrane proximal cysteine residue required for homodimerization and is supposed to exist as monomer on the cell surface as well as in solution.Meanwhile, PD-1 lacks the proline-rich ligand binding motif presenting in all CD28,CTLA-4 and ICOS receptors, which is responsible for the interaction with B7-1 (CD80) and B7-2(CD86), suggesting differences in the mode of ligand recognition and a distinct signaling mechanism.The PD-1 cytoplasmic domain has two tyrosine residues.The membrane-proximal one constitutes an immunoreceptor tyrosine-based inhibitory motif (ITIM) and the other an immunoreceptor tyrosine-based switch motif (ITSM).Because ITIM is widely found in immunoinhibitory receptors including CD72, FcγRIIB and killer cell immunoglobulin-like receptors (KIR), the membrane-proximal tyrosine residue was supposed to play a central role for the inhibitory function of PD-1.However, in vitro experiments using a murine B cell line expressing various mutants of PD-1 reveal that the tyrosine residue located within ITSM and ITIM is essential for the inhibitory function of PD-1 [1].(https://www.daowen.com)

PD-1 is expressed on activated T cells, B cells, myeloid cells, thymocytes, natural killer (NK) cells and on CD4-CD8-thymocytes in the transition from the double-negative to the double-positive stage.The broader expression of PD-1 contrasts with restricted expression of other CD28 family members to T cells, suggesting that PD-1 regulates a wider spectrum of immune responses compared with other CD28 family members.