Function of MiR-146a in Controlling Treg Cell-mediated Regulation of Th1 Responses

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Sep 21

PMID 20850013

Citations 501

Authors

Li-Fan Lu

Mark P Boldin

Ashutosh Chaudhry

Ling-Li Lin

Konstantin D Taganov

Toshikatsu Hanada

Akihiko Yoshimura

David Baltimore

Alexander Y Rudensky

Affiliations

Soon will be listed here.

Abstract

Foxp3(+) regulatory T (Treg) cells maintain immune homeostasis by limiting different types of inflammatory responses. Here, we report that miR-146a, one of the miRNAs prevalently expressed in Treg cells, is critical for their suppressor function. The deficiency of miR-146a in Treg cells resulted in a breakdown of immunological tolerance manifested in fatal IFNγ-dependent immune-mediated lesions in a variety of organs. This was likely due to augmented expression and activation of signal transducer and activator transcription 1 (Stat1), a direct target of miR-146a. Likewise, heightened Stat1 activation in Treg cells subjected to a selective ablation of SOCS1, a key negative regulator of Stat1 phosphorylation downstream of the IFNγ receptor, was associated with analogous Th1-mediated pathology. Our results suggest that specific aspects of Treg suppressor function are controlled by a single miRNA and that an optimal range of Stat1 activation is important for Treg-mediated control of Th1 responses and associated autoimmunity.

Citing Articles

Systematic review of bidirectional interaction between gut microbiome, miRNAs, and human pathologies.

Drago L, De La Motte L, Deflorio L, Sansico D, Salvatici M, Micaglio E Front Microbiol. 2025; 16:1540943.

PMID: 39973938 PMC: 11835932. DOI: 10.3389/fmicb.2025.1540943.

Exploring microRNA-Mediated Immune Responses to Soil-Transmitted Helminth and Herpes Simplex Virus Type 2 Co-Infections.

Pillay R, Naidoo P, Mkhize-Kwitshana Z Diseases. 2025; 13(1).

PMID: 39851470 PMC: 11765296. DOI: 10.3390/diseases13010006.

Oral Delivery of miR146a Conjugated to Cerium Oxide Nanoparticles Improves an Established T Cell-Mediated Experimental Colitis in Mice.

Apte A, Dey P, Julakanti S, Midura-Kiela M, Skopp S, Canchis J Pharmaceutics. 2025; 16(12.

PMID: 39771552 PMC: 11679827. DOI: 10.3390/pharmaceutics16121573.

Circulating microRNAs as a Prognostic Tool to Determine Treatment Efficacy in Lung Cancer Patients Undergoing Pembrolizumab PD-1 Blockade Immunotherapy.

Mohamed Mansoor M, Zhu X, Ashiqueali S, Alam M, Winiarska H, Pazdrowski P Cancers (Basel). 2025; 16(24.

PMID: 39766101 PMC: 11674096. DOI: 10.3390/cancers16244202.

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.

References

Thai T, Calado D, Casola S, Ansel K, Xiao C, Xue Y . Regulation of the germinal center response by microRNA-155. Science. 2007; 316(5824):604-8. DOI: 10.1126/science.1141229. View

Sakaguchi S . Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005; 6(4):345-52. DOI: 10.1038/ni1178. View

Jazdzewski K, Murray E, Franssila K, Jarzab B, Schoenberg D, de la Chapelle A . Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci U S A. 2008; 105(20):7269-74. PMC: 2438239. DOI: 10.1073/pnas.0802682105. View

Lal A, Navarro F, Maher C, Maliszewski L, Yan N, ODay E . miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to "seedless" 3'UTR microRNA recognition elements. Mol Cell. 2009; 35(5):610-25. PMC: 2757794. DOI: 10.1016/j.molcel.2009.08.020. View

Alexander W, Starr R, Fenner J, Scott C, Handman E, Sprigg N . SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell. 1999; 98(5):597-608. DOI: 10.1016/s0092-8674(00)80047-1. View

Marson A, Kretschmer K, Frampton G, Jacobsen E, Polansky J, MacIsaac K . Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature. 2007; 445(7130):931-5. PMC: 3008159. DOI: 10.1038/nature05478. View

Kubo M, Hanada T, Yoshimura A . Suppressors of cytokine signaling and immunity. Nat Immunol. 2003; 4(12):1169-76. DOI: 10.1038/ni1012. View

Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S, Zacharioudaki V . The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity. 2009; 31(2):220-31. PMC: 2865583. DOI: 10.1016/j.immuni.2009.06.024. View

Siebler J, Wirtz S, Klein S, Protschka M, Blessing M, Galle P . A key pathogenic role for the STAT1/T-bet signaling pathway in T-cell-mediated liver inflammation. Hepatology. 2003; 38(6):1573-80. DOI: 10.1016/j.hep.2003.09.020. View

10.

Oldenhove G, Bouladoux N, Wohlfert E, Hall J, Chou D, Dos Santos L . Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity. 2009; 31(5):772-86. PMC: 2814877. DOI: 10.1016/j.immuni.2009.10.001. View

11.

Rubtsov Y, Rasmussen J, Chi E, Fontenot J, Castelli L, Ye X . Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008; 28(4):546-58. DOI: 10.1016/j.immuni.2008.02.017. View

12.

Liston A, Lu L, OCarroll D, Tarakhovsky A, Rudensky A . Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med. 2008; 205(9):1993-2004. PMC: 2526195. DOI: 10.1084/jem.20081062. View

13.

Zhan Y, Davey G, Graham K, Kiu H, Dudek N, Kay T . SOCS1 negatively regulates the production of Foxp3+ CD4+ T cells in the thymus. Immunol Cell Biol. 2009; 87(6):473-80. DOI: 10.1038/icb.2009.23. View

14.

Chong M, Rasmussen J, Rudensky A, Rundensky A, Littman D . The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med. 2008; 205(9):2005-17. PMC: 2526196. DOI: 10.1084/jem.20081219. View

15.

Zhou X, Bailey-Bucktrout S, Jeker L, Penaranda C, Martinez-Llordella M, Ashby M . Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009; 10(9):1000-7. PMC: 2729804. DOI: 10.1038/ni.1774. View

16.

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

17.

Zheng Y, Josefowicz S, Kas A, Chu T, Gavin M, Rudensky A . Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature. 2007; 445(7130):936-40. DOI: 10.1038/nature05563. View

18.

Curtale G, Citarella F, Carissimi C, Goldoni M, Carucci N, Fulci V . An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes. Blood. 2009; 115(2):265-73. DOI: 10.1182/blood-2009-06-225987. View

19.

Zheng Y, Chaudhry A, Kas A, deRoos P, Kim J, Chu T . Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature. 2009; 458(7236):351-6. PMC: 2864791. DOI: 10.1038/nature07674. View

20.

Barbi J, Oghumu S, Lezama-Davila C, Satoskar A . IFN-gamma and STAT1 are required for efficient induction of CXC chemokine receptor 3 (CXCR3) on CD4+ but not CD8+ T cells. Blood. 2007; 110(6):2215-6. PMC: 1976351. DOI: 10.1182/blood-2007-03-081307. View