An immune response is regulated through different mechanisms,
14 including regulatory costimulatory molecules.
15 The balance between the positive and negative signaling costimulatory pathways dictates the fate of individual T cells and the immune response. As a member of the CD28/B7 family and costimulatory molecules, PD-1 interacts with its ligands and constitutes a recently discovered inhibitory regulatory pathway.
16 17 18 PD-1 was originally identified by Ishida et al.
19 as a molecule linked to in vitro induction of apoptotic cell death in murine lymphoid cell lines. PD-1 contains an immunoreceptor tyrosine–based inhibiting motif (ITIM) and an immunoreceptor tyrosine–based switch motif (ITSM)
20 and is transcriptionally induced in activated T cells, B cells, and myeloid cells, suggesting that it has broader roles in immune regulation.
21 22 The ligands for PD-1 (PD-Ls) are PD-L1 and PD-L2, also known as B7-H1 and B7-DC. PD-L1 is constitutively expressed in T cells, B cells, macrophages, dendritic cells (DCs) and nonlymphoid cells, whereas PD-L2 is expressed restrictedly in activated macrophages and DCs.
23 24 25 26 Previous studies have demonstrated that PD-1
−/− C57BL/6 mice develop lupuslike arthritis and glomerulonephritis
27 and that PD-1
−/− BALB/c mice develop autoantibody-mediated dilated cardiomyopathy.
28 Blockade of the PD-1 ligand during experimental autoimmune encephalomyelitis or diabetes was shown to exacerbate these diseases.
29 30 Polymorphisms in the human
PD-1 gene (
PDCD1) are associated with the development of systemic lupus erythematosus, rheumatoid arthritis, diabetes, and multiple sclerosis.
31 32 33 34 Like CTLA-4, the ligation of PD-1 on T cells suppresses T-cell proliferation and cytokine production.
35 36 Moreover, this pathway has been implicated in blocking allograft rejection, modulating T- and B-cell–dependent pathologic immune responses, and inducing transplantation tolerance.
16 37 38 All the results emphasize the importance of the PD-1/PD-L pathway in down-modulating immune responses and in inducing and maintaining peripheral tolerance.