TY - JOUR
T1 - Function of miR-146a in Controlling Treg Cell-Mediated Regulation of Th1 Responses
AU - Lu, Li Fan
AU - Boldin, Mark P.
AU - Chaudhry, Ashutosh
AU - Lin, Ling Li
AU - Taganov, Konstantin D.
AU - Hanada, Toshikatsu
AU - Yoshimura, Akihiko
AU - Baltimore, David
AU - Rudensky, Alexander Y.
N1 - Funding Information:
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.
PY - 2010/9
Y1 - 2010/9
N2 - 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.
AB - 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.
KW - Cellimmuno
KW - Humdisease
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U2 - 10.1016/j.cell.2010.08.012
DO - 10.1016/j.cell.2010.08.012
M3 - Article
C2 - 20850013
AN - SCOPUS:77956632634
SN - 0092-8674
VL - 142
SP - 914
EP - 929
JO - Cell
JF - Cell
IS - 6
ER -