MiR-181a/b-1 Controls Thymic Selection of Treg Cells and Tunes Their Suppressive Capacity

Overview

Journal PLoS Biol

Specialty Biology

Date 2019 Mar 12

PMID 30856173

Citations 24

Authors

Marcin Lyszkiewicz

Samantha J Winter

Katrin Witzlau

Lisa Fohse

Rebecca Brownlie

Jacek Puchalka

Nikita A Verheyden

Heike Kunze-Schumacher

Esther Imelmann

Jonas Blume

Solaiman Raha

Takashi Sekiya

Akihiko Yoshimura

Jochen T Frueh

Evelyn Ullrich

Jochen Huehn

Siegfried Weiss

Maximiliano G Gutierrez

Immo Prinz

Rose Zamoyska

Natalia Zietara

Andreas Krueger

Affiliations

Soon will be listed here.

Abstract

The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1-deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte-associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.

Citing Articles

Bidirectional Interplay Among Non-Coding RNAs, the Microbiome, and the Host During Development and Diseases.

Nai S, Song J, Su W, Liu X Genes (Basel). 2025; 16(2).

PMID: 40004537 PMC: 11855195. DOI: 10.3390/genes16020208.

The functions of immune system-derived miRNAs in cardiovascular diseases.

Sufianov A, Agaverdiev M, Mashkin A, Ilyasova T Noncoding RNA Res. 2024; 11:91-103.

PMID: 39736852 PMC: 11683256. DOI: 10.1016/j.ncrna.2024.11.004.

Infiltrating treg reprogramming in the tumor immune microenvironment and its optimization for immunotherapy.

Zhou Z, Xu J, Liu S, Lv Y, Zhang R, Zhou X Biomark Res. 2024; 12(1):97.

PMID: 39227959 PMC: 11373505. DOI: 10.1186/s40364-024-00630-9.

The Role of the MiR-181 Family in Hepatocellular Carcinoma.

Chen J, Liu K, Vadas M, Gamble J, McCaughan G Cells. 2024; 13(15.

PMID: 39120319 PMC: 11311592. DOI: 10.3390/cells13151289.

A high-resolution map of functional miR-181 response elements in the thymus reveals the role of coding sequence targeting and an alternative seed match.

Verheyden N, Klostermann M, Bruggemann M, Steede H, Scholz A, Amr S Nucleic Acids Res. 2024; 52(14):8515-8533.

PMID: 38783381 PMC: 11317165. DOI: 10.1093/nar/gkae416.

References

Schaffert S, Loh C, Wang S, Arnold C, Axtell R, Newell E . mir-181a-1/b-1 Modulates Tolerance through Opposing Activities in Selection and Peripheral T Cell Function. J Immunol. 2015; 195(4):1470-9. PMC: 4763610. DOI: 10.4049/jimmunol.1401587. View

Kirigin F, Lindstedt K, Sellars M, Ciofani M, Low S, Jones L . Dynamic microRNA gene transcription and processing during T cell development. J Immunol. 2012; 188(7):3257-67. PMC: 3934760. DOI: 10.4049/jimmunol.1103175. View

Tai X, Erman B, Alag A, Mu J, Kimura M, Katz G . Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity. 2013; 38(6):1116-28. PMC: 3700677. DOI: 10.1016/j.immuni.2013.02.022. View

Winter S, Kunze-Schumacher H, Imelmann E, Grewers Z, Osthues T, Krueger A . MicroRNA miR-181a/b-1 controls MAIT cell development. Immunol Cell Biol. 2018; 97(2):190-202. DOI: 10.1111/imcb.12211. View

Hsieh C, Liang Y, Tyznik A, Self S, Liggitt D, Rudensky A . Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity. 2004; 21(2):267-77. DOI: 10.1016/j.immuni.2004.07.009. View

Zietara N, Lyszkiewicz M, Witzlau K, Naumann R, Hurwitz R, Langemeier J . Critical role for miR-181a/b-1 in agonist selection of invariant natural killer T cells. Proc Natl Acad Sci U S A. 2013; 110(18):7407-12. PMC: 3645533. DOI: 10.1073/pnas.1221984110. View

Fulton R, Hamilton S, Xing Y, Best J, Goldrath A, Hogquist K . The TCR's sensitivity to self peptide-MHC dictates the ability of naive CD8(+) T cells to respond to foreign antigens. Nat Immunol. 2014; 16(1):107-17. PMC: 4270846. DOI: 10.1038/ni.3043. View

Azzam H, Grinberg A, Lui K, Shen H, Shores E, Love P . CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J Exp Med. 1998; 188(12):2301-11. PMC: 2212429. DOI: 10.1084/jem.188.12.2301. View

Ebert P, Jiang S, Xie J, Li Q, Davis M . An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat Immunol. 2009; 10(11):1162-9. PMC: 3762483. DOI: 10.1038/ni.1797. View

10.

Sekiya T, Kashiwagi I, Yoshida R, Fukaya T, Morita R, Kimura A . Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis. Nat Immunol. 2013; 14(3):230-7. DOI: 10.1038/ni.2520. View

11.

Duber S, Hafner M, Krey M, Lienenklaus S, Roy B, Hobeika E . Induction of B-cell development in adult mice reveals the ability of bone marrow to produce B-1a cells. Blood. 2009; 114(24):4960-7. DOI: 10.1182/blood-2009-04-218156. View

12.

Khattri R, Cox T, Yasayko S, Ramsdell F . An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003; 4(4):337-42. DOI: 10.1038/ni909. View

13.

Siggs O, Miosge L, Yates A, Kucharska E, Sheahan D, Brdicka T . Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions. Immunity. 2007; 27(6):912-26. PMC: 3163119. DOI: 10.1016/j.immuni.2007.11.013. View

14.

Blume J, Zur Lage S, Witzlau K, Georgiev H, Weiss S, Lyszkiewicz M . Overexpression of Vα14Jα18 TCR promotes development of iNKT cells in the absence of miR-181a/b-1. Immunol Cell Biol. 2016; 94(8):741-6. DOI: 10.1038/icb.2016.40. View

15.

Hinterberger M, Aichinger M, Prazeres da Costa O, Voehringer D, Hoffmann R, Klein L . Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat Immunol. 2010; 11(6):512-9. DOI: 10.1038/ni.1874. View

16.

Cobb B, Hertweck A, Smith J, OConnor E, Graf D, Cook T . A role for Dicer in immune regulation. J Exp Med. 2006; 203(11):2519-27. PMC: 2118134. DOI: 10.1084/jem.20061692. View

17.

Wirnsberger G, Mair F, Klein L . Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control. Proc Natl Acad Sci U S A. 2009; 106(25):10278-83. PMC: 2694684. DOI: 10.1073/pnas.0901877106. View

18.

Burchill M, Yang J, Vang K, Moon J, Chu H, Lio C . Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity. 2008; 28(1):112-21. PMC: 2430111. DOI: 10.1016/j.immuni.2007.11.022. View

19.

Simons D, Cozzo Picca C, Oh S, Perng O, Aitken M, Erikson J . How specificity for self-peptides shapes the development and function of regulatory T cells. J Leukoc Biol. 2010; 88(6):1099-107. PMC: 2996893. DOI: 10.1189/jlb.0310183. View

20.

Apostolou I, Sarukhan A, Klein L, von Boehmer H . Origin of regulatory T cells with known specificity for antigen. Nat Immunol. 2002; 3(8):756-63. DOI: 10.1038/ni816. View