Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2018 Nov 3

PMID 30386337

Citations 105

Authors

Elena Gianchecchi

Alessandra Fierabracci

Affiliations

Soon will be listed here.

Abstract

Regulatory T (Treg) cells represent a subpopulation of suppressor CD4 T cells critically involved in the establishment of peripheral tolerance through the inhibition of effector T (Teff) cells and the suppression of the immune-mediated tissue destruction toward self-antigens. Treg generation, their suppressive properties and also Treg-Teff cell interactions could be modulated at least in part by programmed cell death-1 (PD-1) expression on their surface and through binding between PD-1 and programmed cell death ligand-1 (PD-L1). Defects involving PD-1 and Tregs can lead to the development of pathological conditions, including autoimmune disorders or promote cancer progression by favoring tumor evasion from the host immune response. At the same time, PD-1 and Tregs could represent attractive targets for treatment, as demonstrated by the therapeutic blockade of PD-L1 applied for the management of different cancer conditions in humans. In the present Review, we focus specifically the role of PD-1/PD-L1 on Treg development and activity.

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References

Mesquita Jr D, Cruvinel W, Araujo J, Salmazi K, Kallas E, Andrade L . Imbalanced expression of functional surface molecules in regulatory and effector T cells in systemic lupus erythematosus. Braz J Med Biol Res. 2014; 47(8):662-9. PMC: 4165293. DOI: 10.1590/1414-431x20143483. View

Krupnick A, Gelman A, Barchet W, Richardson S, Kreisel F, Turka L . Murine vascular endothelium activates and induces the generation of allogeneic CD4+25+Foxp3+ regulatory T cells. J Immunol. 2005; 175(10):6265-70. DOI: 10.4049/jimmunol.175.10.6265. View

Wolchok J, Kluger H, Callahan M, Postow M, Rizvi N, Lesokhin A . Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013; 369(2):122-33. PMC: 5698004. DOI: 10.1056/NEJMoa1302369. View

Ahmadzadeh M, Johnson L, Heemskerk B, Wunderlich J, Dudley M, White D . Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009; 114(8):1537-44. PMC: 2927090. DOI: 10.1182/blood-2008-12-195792. View

Nedoszytko B, Lange M, Sokolowska-Wojdylo M, Renke J, Trzonkowski P, Sobjanek M . The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part I: Treg properties and functions. Postepy Dermatol Alergol. 2017; 34(4):285-294. PMC: 5560174. DOI: 10.5114/ada.2017.69305. View

KUNIYASU Y, Takahashi T, Itoh M, Shimizu J, Toda G, Sakaguchi S . Naturally anergic and suppressive CD25(+)CD4(+) T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. Int Immunol. 2000; 12(8):1145-55. DOI: 10.1093/intimm/12.8.1145. View

Gotot J, Gottschalk C, Leopold S, Knolle P, Yagita H, Kurts C . Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo. Proc Natl Acad Sci U S A. 2012; 109(26):10468-73. PMC: 3387068. DOI: 10.1073/pnas.1201131109. View

Miao X, Xu R, Fan B, Chen J, Li X, Mao W . PD-L1 reverses depigmentation in Pmel-1 vitiligo mice by increasing the abundance of Tregs in the skin. Sci Rep. 2018; 8(1):1605. PMC: 5785514. DOI: 10.1038/s41598-018-19407-w. View

Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H . Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996; 8(5):765-72. DOI: 10.1093/intimm/8.5.765. View

10.

Ishida Y, Agata Y, Shibahara K, Honjo T . Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992; 11(11):3887-95. PMC: 556898. DOI: 10.1002/j.1460-2075.1992.tb05481.x. View

11.

Care A, Bourque S, Morton J, Hjartarson E, Robertson S, Davidge S . Reduction in Regulatory T Cells in Early Pregnancy Causes Uterine Artery Dysfunction in Mice. Hypertension. 2018; 72(1):177-187. DOI: 10.1161/HYPERTENSIONAHA.118.10858. View

12.

Iwai Y, Hamanishi J, Chamoto K, Honjo T . Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci. 2017; 24(1):26. PMC: 5381059. DOI: 10.1186/s12929-017-0329-9. View

13.

Szymczak-Workman A, Workman C, Vignali D . Cutting edge: regulatory T cells do not require stimulation through their TCR to suppress. J Immunol. 2009; 182(9):5188-92. PMC: 2745156. DOI: 10.4049/jimmunol.0803123. View

14.

Sharpe A, Wherry E, Ahmed R, Freeman G . The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007; 8(3):239-45. DOI: 10.1038/ni1443. View

15.

Chen W, Jin W, Hardegen N, Lei K, Li L, Marinos N . Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003; 198(12):1875-86. PMC: 2194145. DOI: 10.1084/jem.20030152. View

16.

Saito M, Shiraishi K, Goto A, Suzuki H, Kohno T, Kono K . Development of targeted therapy and immunotherapy for treatment of small cell lung cancer. Jpn J Clin Oncol. 2018; 48(7):603-608. DOI: 10.1093/jjco/hyy068. View

17.

Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T . Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010; 107(17):7875-80. PMC: 2867907. DOI: 10.1073/pnas.1003345107. View

18.

Topalian S, Taube J, Anders R, Pardoll D . Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer. 2016; 16(5):275-87. PMC: 5381938. DOI: 10.1038/nrc.2016.36. View

19.

Fujimura T, Ring S, Umansky V, Mahnke K, Enk A . Regulatory T cells stimulate B7-H1 expression in myeloid-derived suppressor cells in ret melanomas. J Invest Dermatol. 2011; 132(4):1239-46. DOI: 10.1038/jid.2011.416. View

20.

Mitsui J, Nishikawa H, Muraoka D, Wang L, Noguchi T, Sato E . Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin Cancer Res. 2010; 16(10):2781-91. DOI: 10.1158/1078-0432.CCR-09-3243. View