The PD-1 Pathway in Tolerance and Autoimmunity

By Loise M. Francisco, P. Sage, Arlene H. Sharpe. Immunological Reviews, 2010

2,180 citations recorded by the source corpus.

Summary: Regulatory T cells (Tregs) and the PD‐1: PD‐ligand (PD‐L) pathway are both critical to terminating immune responses. Elimination of either can result in the breakdown of tolerance and the development of autoimmunity. The PD‐1: PD‐L pathway can thwart self‐reactive T cells and protect against autoimmunity in many ways. In this review, we highlight how PD‐1 and its ligands defend against potentially pathogenic self‐reactive effector T cells by simultaneously harnessing two mechanisms of peripheral tolerance: (i) the promotion of Treg development and function and (ii) the direct inhibition of potentially pathogenic self‐reactive T cells that have escaped into the periphery. Treg cells induced by the PD‐1 pathway may also assist in maintaining immune homeostasis, keeping the threshold for T‐cell activation high enough to safeguard against autoimmunity. PD‐L1 expression on non‐hematopoietic cells as well as hematopoietic cells endows PD‐L1 with the capacity to promote Treg development and enhance Treg function in lymphoid organs and tissues that are targets of autoimmune attack. At sites where transforming growth factor‐β is present (e.g. sites of immune privilege or inflammation), PD‐L1 may promote the de novo generation of Tregs. When considering the consequences of uncontrolled immunity, it would be therapeutically advantageous to manipulate Treg development and sustain Treg function. Thus, this review also discusses how the PD‐1 pathway regulates a number of autoimmune diseases and the therapeutic potential of PD‐1: PD‐L modulation.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/13b43578e8390a54e624056b894a42c74009c31a

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Citations in the corpus

Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1 (2016, background): “Alternatively, immune compensatorymechanisms through the upregulation of alternative immune checkpoints or the modulation of other protumor immune subsets could have occurred (30, 31).”
Metabolic competition in the tumor microenvironment is a driver of cancer progression (2015, background): “PD-L1 Directly Regulates Tumor Metabolism IFN-g fromTcells inducesPD-L1on tumors, andPD-L1canallow the tumor to evade immune mediated attack by inhibiting T cell function through PD-1/PD-L1 interaction (Francisco et al., 2010; Keir et al., 2008).”
Mechanisms controlling PD-L1 expression in cancer (2019, background): “To prevent such autoimmune reactions, co-inhibitory immune checkpoint proteins, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death-1 (PD-1; encoded by the PDCD1 gene), and programmed death-ligand (PD-L1; encoded by the CD274 gene), maintain an intricate regulation of T-ce”
PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome (2017, background): “They suppress the Tcells and increase the production of the regulatory T-cells, thus reducing the auto-immunity and improving the tolerance (Francisco et al., 2010) of some of these ligands promote the complement-dependent cytotoxicity.”
Combination of CTLA-4 and PD-1 blockers for treatment of cancer (2019, background): “Through inhibition of PI3K pathway, PD-1 signaling was shown to prevent activation of the cell survival factor Bcl-xL and abrogate the expression of transcription factors that regulate the effector functions of T-cells such as GATA-3, T-bet and Eomes [44].”
PD-L1 expression in human cancers and its association with clinical outcomes (2016, neutral): “PD-L1 receptor is also expressed on the surface of CD4+Foxp3+ regulatory T cells (Tregs), a subset of CD4+ T cells that play a critical role in maintaining immune tolerance and weakening immune responses, to promote the development, maintenance, and immunosuppressive function of Tregs through inhibi”
Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “(III) Signaling of PD-L1 within cancer cells may prevent the apoptosis of tumor cells themselves, and the interaction of PD-L1 with CD80 can suppress the immune response, etc [70].”