PD-L1 Regulates the Development, Maintenance, and Function of Induced Regulatory T Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2009 Dec 17

PMID 20008522

Citations 1088

Authors

Loise M Francisco

Victor H Salinas

Keturah E Brown

Vijay K Vanguri

Gordon J Freeman

Vijay K Kuchroo

Arlene H Sharpe

Affiliations

Soon will be listed here.

Abstract

Both the programmed death (PD) 1-PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1(-/-) antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1-coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1(-/-)PD-L2(-/-) Rag(-/-) recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.

Citing Articles

Breaking Immunosuppression to Enhance Cancer Stem Cell-Targeted Immunotherapy.

Zheng F, Zhang S, Chang A, Moon J, Wicha M, Wang S Int J Biol Sci. 2025; 21(4):1819-1836.

PMID: 39990669 PMC: 11844285. DOI: 10.7150/ijbs.101025.

PD-L1/PD-L2 genetic profile in the molecular cytogenetic classification of classic Hodgkin lymphoma.

Garcia-Montenegro M, Narbaitz M, Metrebian M, Pavlovsky A, Slavutsky I Virchows Arch. 2025; .

PMID: 39976683 DOI: 10.1007/s00428-025-04047-z.

Regulatory T cells in the tumor microenvironment display a unique chromatin accessibility profile.

Dadey R, Cui J, Rajasundaram D, Yano H, Liu C, Cohen J Immunohorizons. 2025; 9(4).

PMID: 39965167 PMC: 11841976. DOI: 10.1093/immhor/vlae014.

Flow cytometry immune profiling of recurrent and newly diagnosed growth hormone secreting pituitary neuroendocrine tumors: comparison of two clinical cases.

Lisina D, Mazeeva V, Zakharova E, Sorokina A, Dzhemileva L, Grigoriev A BMC Endocr Disord. 2025; 25(1):37.

PMID: 39939927 PMC: 11816545. DOI: 10.1186/s12902-025-01865-9.

Immune Checkpoints Are New Therapeutic Targets in Regulating Cardio-, and Cerebro-Vascular Diseases and CD4Foxp3 Regulatory T Cell Immunosuppression.

Shao Y, Yang W, Nanayakkara G, Saaoud F, Ben Issa M, Xu K Int J Drug Discov Pharm. 2025; 3(4).

PMID: 39926714 PMC: 11804271. DOI: 10.53941/ijddp.2024.100022.

References

Calzascia T, Pellegrini M, Lin A, Garza K, Elford A, Shahinian A . CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Proc Natl Acad Sci U S A. 2008; 105(8):2999-3004. PMC: 2268574. DOI: 10.1073/pnas.0712135105. View

Sakaguchi S, Yamaguchi T, Nomura T, Ono M . Regulatory T cells and immune tolerance. Cell. 2008; 133(5):775-87. DOI: 10.1016/j.cell.2008.05.009. View

Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M . B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004; 10(15):5094-100. DOI: 10.1158/1078-0432.CCR-04-0428. View

Long S, Buckner J . Combination of rapamycin and IL-2 increases de novo induction of human CD4(+)CD25(+)FOXP3(+) T cells. J Autoimmun. 2008; 30(4):293-302. PMC: 2431984. DOI: 10.1016/j.jaut.2007.12.012. View

Collison L, Workman C, Kuo T, Boyd K, Wang Y, Vignali K . The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007; 450(7169):566-9. DOI: 10.1038/nature06306. View

Inman B, Sebo T, Frigola X, Dong H, Bergstralh E, Frank I . PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007; 109(8):1499-505. DOI: 10.1002/cncr.22588. View

Liang S, Alard P, Zhao Y, Parnell S, Clark S, Kosiewicz M . Conversion of CD4+ CD25- cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med. 2005; 201(1):127-37. PMC: 2212775. DOI: 10.1084/jem.20041201. View

Pyzik M, Piccirillo C . TGF-beta1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets. J Leukoc Biol. 2007; 82(2):335-46. DOI: 10.1189/jlb.1006644. View

Tang Q, Henriksen K, Boden E, Tooley A, Ye J, Subudhi S . Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol. 2003; 171(7):3348-52. DOI: 10.4049/jimmunol.171.7.3348. View

10.

Vignali D, Collison L, Workman C . How regulatory T cells work. Nat Rev Immunol. 2008; 8(7):523-32. PMC: 2665249. DOI: 10.1038/nri2343. View

11.

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

12.

Bettelli E, Carrier Y, Gao W, Korn T, Strom T, Oukka M . Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-8. DOI: 10.1038/nature04753. View

13.

Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M . T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A. 2008; 105(22):7797-802. PMC: 2409380. DOI: 10.1073/pnas.0800928105. View

14.

Clark L, Appleby M, Brunkow M, Wilkinson J, Ziegler S, Ramsdell F . Cellular and molecular characterization of the scurfy mouse mutant. J Immunol. 1999; 162(5):2546-54. View

15.

Fantini M, Becker C, Monteleone G, Pallone F, Galle P, Neurath M . Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004; 172(9):5149-53. DOI: 10.4049/jimmunol.172.9.5149. View

16.

Broeren C, GRAY G, Carreno B, June C . Costimulation light: activation of CD4+ T cells with CD80 or CD86 rather than anti-CD28 leads to a Th2 cytokine profile. J Immunol. 2000; 165(12):6908-14. DOI: 10.4049/jimmunol.165.12.6908. View

17.

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

18.

Hori S, Nomura T, Sakaguchi S . Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003; 299(5609):1057-61. DOI: 10.1126/science.1079490. View

19.

Huber S, Schrader J, Fritz G, Presser K, Schmitt S, Waisman A . P38 MAP kinase signaling is required for the conversion of CD4+CD25- T cells into iTreg. PLoS One. 2008; 3(10):e3302. PMC: 2553190. DOI: 10.1371/journal.pone.0003302. View

20.

Coenen J, Koenen H, van Rijssen E, Kasran A, Boon L, Hilbrands L . Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+ CD25+ FoxP3+ T cells. Bone Marrow Transplant. 2007; 39(9):537-45. DOI: 10.1038/sj.bmt.1705628. View