Abstract
The recent success of PD-1 and PD-L1 blockade in cancer therapy illustrates the important role of the PD-1/PD-L1 pathway in the regulation of antitumor immune responses. However, signaling regulated by the PD-1/PD-L pathway is also associated with substantial inflammatory effects that can resemble those in autoimmune responses, chronic infection, and sepsis, consistent with the role of this pathway in balancing protective immunity and immunopathology, as well as in homeostasis and tolerance. Targeting PD-1/PD-L1 to treat cancer has shown benefits in many patients, suggesting a promising opportunity to target this pathway in autoimmune and inflammatory disorders. Here, we systematically evaluate the diverse biological functions of the PD-1/PD-L pathway in immune-mediated diseases and the relevant mechanisms that control these immune reactions.
Highlights
Immune checkpoint inhibitory receptors [such as cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1)] expressed on immune cells trigger immunosuppressive signaling pathways
Peripheral blood monocytes from patients with sepsis showed increased levels of PD-L1, and binding with PD-1 reduced cell survival and function, while treatment with anti-PD-1 antibody restored the production of the key cytokines IFN-γ and IL-2 by monocytes (Table 1) [93]
The current study demonstrated that the enhanced post-stroke inflammation and brain injury are due to the decreased number of CD8+CD12+ suppressor T cells in the central nervous system (CNS), which are PD-L1-dependent
Summary
Immune checkpoint inhibitory receptors [such as cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1)] expressed on immune cells trigger immunosuppressive signaling pathways. PD-1 binds to PD-L1 or PD-L2 and resists positive signals through T-cell receptors (TCRs) and CD28 [2] These immunosuppressive molecules function as brakes to regulate the adaptive immune response. PD-1/PDL1 signaling plays a vital role in immune tolerance and T-cell exhaustion and has emerged as a key target in the treatment of cancer. In different murine colitis models [dextran sulfate sodium (DSS)-induced and T cell-induced colitis], administration of PD-L1-Fc reduced the Th17 cell frequency, DC function, and disease activity (Table 1) [81, 82] Consistent with this finding, PD-L1-Fc can mitigate the pathogenesis of immune thrombocytopenia (ITP) by increasing T-cell apoptosis and by suppressing T-cell activation and proliferation and cytokine (IFN-γ, IL-2) production [102]
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