The PD-1-PD-L pathway in immunological tolerance

Since the first observation of spontaneous autoimmune diseases in programmed cell death 1 (PD-1) knockout mice, PD-1 has been postulated to have essential roles in the regulation of autoimmunity but the precise mechanism was largely unknown. Recent studies clearly demonstrated that PD-1 has dual roles in immunological tolerance: induction and maintenance of peripheral tolerance. PD-1 ligands (PD-Ls) on antigen-presenting cells have been shown to switch off autoreactive T cells and induce peripheral tolerance, whereas those on parenchymal cells prevent tissue destruction by suppressing effector T cells to maintain tolerance. In addition, PDA and other immuno-inhibitory receptors have been shown to collaborate in the regulation of tolerance. Here, we review recent studies on the role of PDA in immunological tolerance and discuss possible clinical applications of PD-1 manipulation.