The Role of PD-1 Signaling in Health and Immune-related Diseases

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Jun 1

PMID 37261359

Authors

Ru-Yue Chen

Yun Zhu

Yun-Yan Shen

Qin-Ying Xu

Han-Yun Tang

Ning-Xun Cui

Lu Jiang

Xiao-Mei Dai

Wei-Qing Chen

Qiang Lin

Xiao-Zhong Li

Affiliations

Soon will be listed here.

Abstract

Programmed cell death 1 receptor (PD-1) and its ligands constitute an inhibitory pathway to mediate the mechanism of immune tolerance and provide immune homeostasis. Significantly, the binding partners of PD-1 and its associated ligands are diverse, which facilitates immunosuppression in cooperation with other immune checkpoint proteins. Accumulating evidence has demonstrated the important immunosuppressive role of the PD-1 axis in the tumor microenvironment and in autoimmune diseases. In addition, PD-1 blockades have been approved to treat various cancers, including solid tumors and hematological malignancies. Here, we provide a comprehensive review of the PD-1 pathway, focusing on the structure and expression of PD-1, programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2); the diverse biological functions of PD-1 signaling in health and immune-related diseases (including tumor immunity, autoimmunity, infectious immunity, transplantation immunity, allergy and immune privilege); and immune-related adverse events related to PD-1 and PD-L1 inhibitors.

Citing Articles

Molecular Mechanisms of Immune Regulation: A Review.

Arneth B Cells. 2025; 14(4).

PMID: 39996755 PMC: 11853995. DOI: 10.3390/cells14040283.

Cellular and immune landscape of chronic liver diseases: insights from immunophenotyping.

Soleimani S, Albayrak O, Somay K, Yang H, Yigit B, Ulukan B Front Mol Biosci. 2025; 11:1521811.

PMID: 39944754 PMC: 11813787. DOI: 10.3389/fmolb.2024.1521811.

Expanding the Potential of Circular RNA (CircRNA) Vaccines: A Promising Therapeutic Approach.

Bu T, Yang Z, Zhao J, Gao Y, Li F, Yang R Int J Mol Sci. 2025; 26(1.

PMID: 39796233 PMC: 11722184. DOI: 10.3390/ijms26010379.

Immune Checkpoint Inhibitor-Associated Cutaneous Adverse Events: Mechanisms of Occurrence.

Eshaq A, Flanagan T, Ba Abbad A, Makarem Z, Bokir M, Alasheq A Int J Mol Sci. 2025; 26(1.

PMID: 39795946 PMC: 11719825. DOI: 10.3390/ijms26010088.

Effects of PGK1 on immunoinfiltration by integrated single-cell and bulk RNA-sequencing analysis in sepsis.

Liu Y, Li W, Lei L, Zhou Y, Huang M, Li Y Front Immunol. 2024; 15:1449975.

PMID: 39712033 PMC: 11659135. DOI: 10.3389/fimmu.2024.1449975.

References

Humphries P, Lo W . Two CTLA-4 ligands, separate pHates. Nat Immunol. 2022; 23(9):1297-1299. DOI: 10.1038/s41590-022-01296-x. View

Zhang Y, Ma L, Hu X, Ji J, Mor G, Liao A . The role of the PD-1/PD-L1 axis in macrophage differentiation and function during pregnancy. Hum Reprod. 2018; 34(1):25-36. DOI: 10.1093/humrep/dey347. View

Pushkaran A, K K, T A, Biswas R, Mohan C . Identification of a PD1/PD-L1 inhibitor by structure-based pharmacophore modelling, virtual screening, molecular docking and biological evaluation. Mol Inform. 2023; 42(6):e2200254. DOI: 10.1002/minf.202200254. View

Topalian S, Drake C, Pardoll D . Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015; 27(4):450-61. PMC: 4400238. DOI: 10.1016/j.ccell.2015.03.001. View

Yang N, Liu X, Chen X, Yu S, Yang W, Liu Y . Stem cells from exfoliated deciduous teeth transplantation ameliorates Sjögren's syndrome by secreting soluble PD-L1. J Leukoc Biol. 2021; 111(5):1043-1055. DOI: 10.1002/JLB.6MA0921-752RR. View

Falcone M, Fousteri G . Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance for Prevention of Type 1 Diabetes. Front Endocrinol (Lausanne). 2020; 11:569. PMC: 7466754. DOI: 10.3389/fendo.2020.00569. View

Niedzwiedzka-Rystwej P, Majchrzak A, Aksak-Was B, Serwin K, Czajkowski Z, Grywalska E . Programmed Cell Death-1/Programmed Cell Death-1 Ligand as Prognostic Markers of Coronavirus Disease 2019 Severity. Cells. 2022; 11(12). PMC: 9222173. DOI: 10.3390/cells11121978. View

Niogret C, Birchmeier W, Guarda G . SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling. Front Immunol. 2019; 10:2468. PMC: 6823243. DOI: 10.3389/fimmu.2019.02468. View

Perez-Cruz M, Iliopoulou B, Hsu K, Wu H, Erkers T, Swaminathan K . Immunoregulatory effects of RGMb in gut inflammation. Front Immunol. 2022; 13:960329. PMC: 9676481. DOI: 10.3389/fimmu.2022.960329. View

10.

Jubel J, Barbati Z, Burger C, Wirtz D, Schildberg F . The Role of PD-1 in Acute and Chronic Infection. Front Immunol. 2020; 11:487. PMC: 7105608. DOI: 10.3389/fimmu.2020.00487. View

11.

Spagnuolo A, Gridelli C . "Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer": is there a substantial difference or not?. J Thorac Dis. 2019; 10(Suppl 33):S4065-S4068. PMC: 6297540. DOI: 10.21037/jtd.2018.09.83. View

12.

Ogishi M, Yang R, Aytekin C, Langlais D, Bourgey M, Khan T . Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child. Nat Med. 2021; 27(9):1646-1654. PMC: 8446316. DOI: 10.1038/s41591-021-01388-5. View

13.

Pu Y, Ji Q . Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression. Front Immunol. 2022; 13:874589. PMC: 9110638. DOI: 10.3389/fimmu.2022.874589. View

14.

Jia X, Geng L, Jiang P, Xu H, Nan K, Yao Y . The biomarkers related to immune related adverse events caused by immune checkpoint inhibitors. J Exp Clin Cancer Res. 2020; 39(1):284. PMC: 7734811. DOI: 10.1186/s13046-020-01749-x. View

15.

Ai L, Xu A, Xu J . Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond. Adv Exp Med Biol. 2020; 1248:33-59. DOI: 10.1007/978-981-15-3266-5_3. View

16.

Ni L, Dong C . New B7 Family Checkpoints in Human Cancers. Mol Cancer Ther. 2017; 16(7):1203-1211. PMC: 5568666. DOI: 10.1158/1535-7163.MCT-16-0761. View

17.

Nishimura C, Pulanco M, Cui W, Lu L, Zang X . PD-L1 and B7-1 Cis-Interaction: New Mechanisms in Immune Checkpoints and Immunotherapies. Trends Mol Med. 2020; 27(3):207-219. PMC: 7914151. DOI: 10.1016/j.molmed.2020.10.004. View

18.

Paul P, Das R, Drow T, Nylen E, Henrique de Souza A, Wang Z . Islet allografts expressing a PD-L1 and IDO fusion protein evade immune rejection and reverse preexisting diabetes in immunocompetent mice without systemic immunosuppression. Am J Transplant. 2022; 22(11):2571-2585. PMC: 9804298. DOI: 10.1111/ajt.17162. View

19.

Borghaei H, Ciuleanu T, Lee J, Pluzanski A, Caro R, Gutierrez M . Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Ann Oncol. 2022; 34(2):173-185. DOI: 10.1016/j.annonc.2022.11.006. View

20.

Guleria I, Khosroshahi A, Ansari M, Habicht A, Azuma M, Yagita H . A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med. 2005; 202(2):231-7. PMC: 2213002. DOI: 10.1084/jem.20050019. View