TIGIT-Fc As a Potential Therapeutic Agent for Fetomaternal Tolerance

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Apr 12

PMID 33841433

Citations 6

Authors

Wenyan Fu

Renfei Cai

Zetong Ma

Tian Li

Changhai Lei

Jian Zhao

Shi Hu

Affiliations

Soon will be listed here.

Abstract

The perfect synchronization of maternal immune-endocrine mechanisms and those of the fetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-fetal interface were detected that expressed TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is a co-inhibitory receptor that triggers immunological tolerance. We generated recombinant TIGIT-Fc fusion proteins by linking the extracellular domain of TIGIT and silent Fc fragments. The treatment with TIGIT-Fc of human decidual antigen presenting cells (APCs), the decidual dendritic cells (dDCs), and decidual macrophages (dMϕs) increased the production of interleukin 10 and induced the decidua APCs to powerfully polarize the decidual CD4 T cells toward a classic T2 phenotype. We further proposed that Notch signaling shows a pivotal effect on the transcriptional regulation in decidual immune cell subsets. Moreover, the administration of TIGIT-Fc to CBA/J pregnant mice at preimplantation induced CD4 forkhead box P3 (Foxp3) regulatory T cells and tolerogenic dendritic cells and increased pregnancy rates in an abortion-prone animal model stress. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies.

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References

Williams Z . Inducing tolerance to pregnancy. N Engl J Med. 2012; 367(12):1159-61. PMC: 3644969. DOI: 10.1056/NEJMcibr1207279. View

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

Levin S, Taft D, Brandt C, Bucher C, Howard E, Chadwick E . Vstm3 is a member of the CD28 family and an important modulator of T-cell function. Eur J Immunol. 2011; 41(4):902-15. PMC: 3733993. DOI: 10.1002/eji.201041136. View

Zhu Y, Paniccia A, Schulick A, Chen W, Koenig M, Byers J . Identification of CD112R as a novel checkpoint for human T cells. J Exp Med. 2016; 213(2):167-76. PMC: 4749091. DOI: 10.1084/jem.20150785. View

Johnston R, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y . The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014; 26(6):923-937. DOI: 10.1016/j.ccell.2014.10.018. View

Salvany-Celades M, van der Zwan A, Benner M, Setrajcic-Dragos V, Gomes H, Iyer V . Three Types of Functional Regulatory T Cells Control T Cell Responses at the Human Maternal-Fetal Interface. Cell Rep. 2019; 27(9):2537-2547.e5. DOI: 10.1016/j.celrep.2019.04.109. View

Hu S, Fu W, Li T, Yuan Q, Wang F, Lv G . Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency. Sci Transl Med. 2017; 9(380). DOI: 10.1126/scitranslmed.aag0339. View

Fu W, Lei C, Yu Y, Liu S, Li T, Lin F . EGFR/Notch Antagonists Enhance the Response to Inhibitors of the PI3K-Akt Pathway by Decreasing Tumor-Initiating Cell Frequency. Clin Cancer Res. 2019; 25(9):2835-2847. DOI: 10.1158/1078-0432.CCR-18-2732. View

Liu J, Qian X, Chen Z, Xu X, Gao F, Zhang S . Crystal structure of cell adhesion molecule nectin-2/CD112 and its binding to immune receptor DNAM-1/CD226. J Immunol. 2012; 188(11):5511-20. DOI: 10.4049/jimmunol.1200324. View

10.

Lozano E, Dominguez-Villar M, Kuchroo V, Hafler D . The TIGIT/CD226 axis regulates human T cell function. J Immunol. 2012; 188(8):3869-75. PMC: 3324669. DOI: 10.4049/jimmunol.1103627. View

11.

Tahara-Hanaoka S, Shibuya K, Kai H, Miyamoto A, Morikawa Y, Ohkochi N . Tumor rejection by the poliovirus receptor family ligands of the DNAM-1 (CD226) receptor. Blood. 2005; 107(4):1491-6. DOI: 10.1182/blood-2005-04-1684. View

12.

Rai R, Regan L . Recurrent miscarriage. Lancet. 2006; 368(9535):601-11. DOI: 10.1016/S0140-6736(06)69204-0. View

13.

Fu B, Li X, Sun R, Tong X, Ling B, Tian Z . Natural killer cells promote immune tolerance by regulating inflammatory TH17 cells at the human maternal-fetal interface. Proc Natl Acad Sci U S A. 2012; 110(3):E231-40. PMC: 3549088. DOI: 10.1073/pnas.1206322110. View

14.

Manieri N, Chiang E, Grogan J . TIGIT: A Key Inhibitor of the Cancer Immunity Cycle. Trends Immunol. 2016; 38(1):20-28. DOI: 10.1016/j.it.2016.10.002. View

15.

Stanietsky N, Lenac Rovis T, Glasner A, Seidel E, Tsukerman P, Yamin R . Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. Eur J Immunol. 2013; 43(8):2138-50. PMC: 3863769. DOI: 10.1002/eji.201243072. View

16.

Yu X, Harden K, Gonzalez L, Francesco M, Chiang E, Irving B . The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2008; 10(1):48-57. DOI: 10.1038/ni.1674. View

17.

Joller N, Lozano E, Burkett P, Patel B, Xiao S, Zhu C . Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014; 40(4):569-81. PMC: 4070748. DOI: 10.1016/j.immuni.2014.02.012. View

18.

Kammerer U, Schoppet M, McLellan A, Kapp M, Huppertz H, Kampgen E . Human decidua contains potent immunostimulatory CD83(+) dendritic cells. Am J Pathol. 2000; 157(1):159-69. PMC: 1850207. DOI: 10.1016/S0002-9440(10)64527-0. View

19.

Gorvel L, Ben Amara A, Ka M, Textoris J, Gorvel J, Mege J . Myeloid decidual dendritic cells and immunoregulation of pregnancy: defective responsiveness to Coxiella burnetii and Brucella abortus. Front Cell Infect Microbiol. 2015; 4:179. PMC: 4275036. DOI: 10.3389/fcimb.2014.00179. View

20.

Stengel K, Harden-Bowles K, Yu X, Rouge L, Yin J, Comps-Agrar L . Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc Natl Acad Sci U S A. 2012; 109(14):5399-404. PMC: 3325733. DOI: 10.1073/pnas.1120606109. View