PD-1 and Its Ligands in Tolerance and Immunity

Overview

Journal Annu Rev Immunol

Specialty Allergy & Immunology

Date 2008 Jan 5

PMID 18173375

Citations 2649

Authors

Mary E Keir

Manish J Butte

Gordon J Freeman

Arlene H Sharpe

Affiliations

Soon will be listed here.

Abstract

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.

Citing Articles

Post-translational modifications of immune checkpoints: unlocking new potentials in cancer immunotherapy.

Hu Q, Shi Y, Wang H, Bing L, Xu Z Exp Hematol Oncol. 2025; 14(1):37.

PMID: 40087690 DOI: 10.1186/s40164-025-00627-6.

Revolutionary Cancer Therapy for Personalization and Improved Efficacy: Strategies to Overcome Resistance to Immune Checkpoint Inhibitor Therapy.

Almawash S Cancers (Basel). 2025; 17(5).

PMID: 40075727 PMC: 11899125. DOI: 10.3390/cancers17050880.

Influence of gut microbial metabolites on tumor immunotherapy: mechanisms and potential natural products.

Li D, Lan X, Xu L, Zhou S, Luo H, Zhang X Front Immunol. 2025; 16:1552010.

PMID: 40066456 PMC: 11891355. DOI: 10.3389/fimmu.2025.1552010.

New approach methodologies to assess wanted and unwanted drugs-induced immunostimulation.

Bettinsoli V, Melzi G, Marchese I, Pantaleoni S, Passoni F, Corsini E Curr Res Toxicol. 2025; 8:100222.

PMID: 40027547 PMC: 11872130. DOI: 10.1016/j.crtox.2025.100222.

Effectiveness and safety of PD-1/L1 inhibitors as first-line therapy for patients with advanced or metastatic urothelial carcinoma who are ineligible for platinum-based chemotherapy: a meta-analysis.

Liang W, Wang Z, Huang Z, Huang Y, Li C, Liang Y Front Immunol. 2025; 16:1430673.

PMID: 40013152 PMC: 11860080. DOI: 10.3389/fimmu.2025.1430673.

References

Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T . PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001; 98(24):13866-71. PMC: 61133. DOI: 10.1073/pnas.231486598. View

Day C, Kaufmann D, Kiepiela P, Brown J, Moodley E, Reddy S . PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006; 443(7109):350-4. DOI: 10.1038/nature05115. View

Abe M, Wang Z, De Creus A, Thomson A . Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival. Am J Transplant. 2005; 5(8):1808-19. DOI: 10.1111/j.1600-6143.2005.00954.x. View

Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A . Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001; 291(5502):319-22. DOI: 10.1126/science.291.5502.319. View

Egen J, Allison J . Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002; 16(1):23-35. DOI: 10.1016/s1074-7613(01)00259-x. View

Wang S, Lin C, Ou T, Wu C, Tsai W, Hu C . Ligands for programmed cell death 1 gene in patients with systemic lupus erythematosus. J Rheumatol. 2007; 34(4):721-5. View

Barber D, Wherry E, Masopust D, Zhu B, Allison J, Sharpe A . Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2005; 439(7077):682-7. DOI: 10.1038/nature04444. View

Vadivel N, Trikudanathan S, Chandraker A . Transplant tolerance through costimulation blockade--are we there yet?. Front Biosci. 2007; 12:2935-46. DOI: 10.2741/2283. View

Carter L, Fouser L, Jussif J, Fitz L, Deng B, Wood C . PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol. 2002; 32(3):634-43. DOI: 10.1002/1521-4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9. View

10.

Grabie N, Gotsman I, DaCosta R, Pang H, Stavrakis G, Butte M . Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart. Circulation. 2007; 116(18):2062-71. DOI: 10.1161/CIRCULATIONAHA.107.709360. View

11.

Lafferty K, Cunningham A . A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci. 1975; 53(1):27-42. DOI: 10.1038/icb.1975.3. View

12.

Hori J, Wang M, Miyashita M, Tanemoto K, Takahashi H, Takemori T . B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. J Immunol. 2006; 177(9):5928-35. DOI: 10.4049/jimmunol.177.9.5928. View

13.

Okazaki T, Honjo T . PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007; 19(7):813-24. DOI: 10.1093/intimm/dxm057. View

14.

Dong H, Strome S, Matteson E, Moder K, Flies D, Zhu G . Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J Clin Invest. 2003; 111(3):363-70. PMC: 151851. DOI: 10.1172/JCI16015. View

15.

Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S . Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. 2006; 56(8):1173-82. PMC: 11029839. DOI: 10.1007/s00262-006-0266-z. View

16.

Tivol E, Borriello F, Schweitzer A, Lynch W, Bluestone J, Sharpe A . Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995; 3(5):541-7. DOI: 10.1016/1074-7613(95)90125-6. View

17.

He X, Liu Y, Xu L, Zeng Y . Cloning and identification of two novel splice variants of human PD-L2. Acta Biochim Biophys Sin (Shanghai). 2004; 36(4):284-9. DOI: 10.1093/abbs/36.4.284. View

18.

Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg H, Blum H . Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol. 2006; 80(7):3532-40. PMC: 1440406. DOI: 10.1128/JVI.80.7.3532-3540.2006. View

19.

Iwai Y, Terawaki S, Honjo T . PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 2004; 17(2):133-44. DOI: 10.1093/intimm/dxh194. View

20.

Brown J, Dorfman D, Ma F, Sullivan E, Munoz O, Wood C . Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol. 2003; 170(3):1257-66. DOI: 10.4049/jimmunol.170.3.1257. View