Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses.
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.
Lu
Li-Fan
LF
Howard Hughes Medical Institute and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Boldin
Mark P
MP
Chaudhry
Ashutosh
A
Lin
Ling-Li
LL
Taganov
Konstantin D
KD
Hanada
Toshikatsu
T
Yoshimura
Akihiko
A
Baltimore
David
D
Rudensky
Alexander Y
AY
D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma