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Function of miR-146a in Controlling Treg Cell-Mediated Regulation of Th1 Responses

Lu, Li-Fan and Boldin, Mark P. and Chaudhry, Ashutosh and Lin, Ling-Li and Taganov, Konstantin D. and Hanada, Toshikatsu and Yoshimura, Akihiko and Baltimore, David and Rudensky, Alexander Y. (2010) Function of miR-146a in Controlling Treg Cell-Mediated Regulation of Th1 Responses. Cell, 142 (6). pp. 914-929. ISSN 0092-8674. PMCID PMC3049116. https://resolver.caltech.edu/CaltechAUTHORS:20101012-085533074

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cell.2010.08.012 DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049116PubMed CentralArticle
ORCID:
AuthorORCID
Boldin, Mark P.0000-0003-4593-0669
Baltimore, David0000-0001-8723-8190
Additional Information:© 2010 Elsevier. Received 8 February 2010; revised 20 July 2010; accepted 7 August 2010. Published: September 16, 2010. Available online 16 September 2010. We thank A. Ramos for the help in key experiments, Y. Liang, P. Zarin, A. Bravo, and J. Herlihy for superb technical assistance, and all members of our laboratory for discussions. This work was supported by grants from the NIH (A.Y.R. and D.B.) and from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (A.Y.). L.-F.L. is a Leukemia and Lymphoma Society Fellow. A.C. is a Cancer Research Institute Fellow. A.Y.R. is a Howard Hughes Medical Institute investigator. D.B. is the director and M.P.B. and K.D.T. are employees of Regulus Therapeutics Inc., a company devoted to commercializing therapies directed at microRNAs.
Funders:
Funding AgencyGrant Number
NIHUNSPECIFIED
Ministry of Education, Culture, Sports, Science and Technology (MEXT)UNSPECIFIED
National Institute of Biomedical InnovationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Leukemia and Lymphoma SocietyUNSPECIFIED
Cancer Research InstituteUNSPECIFIED
Issue or Number:6
PubMed Central ID:PMC3049116
Record Number:CaltechAUTHORS:20101012-085533074
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20101012-085533074
Official Citation:Li-Fan Lu, Mark P. Boldin, Ashutosh Chaudhry, Ling-Li Lin, Konstantin D. Taganov, Toshikatsu Hanada, Akihiko Yoshimura, David Baltimore, Alexander Y. Rudensky, Function of miR-146a in Controlling Treg Cell-Mediated Regulation of Th1 Responses, Cell, Volume 142, Issue 6, 2010, Pages 914-929, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2010.08.012. (http://www.sciencedirect.com/science/article/pii/S0092867410009190)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:20392
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:10 Nov 2010 17:46
Last Modified:21 Apr 2020 21:48

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