Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses

By Li-Fan Lu, M. Boldin, A. Chaudhry, Ling-Li Lin, K. Taganov, Toshikatsu Hanada, A. Yoshimura, David Baltimore, Alexander Y. Rudensky. Cell, 2010

953 citations recorded by the source corpus.

Summary 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 a 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 miR146a. Likewise, heightened Stat1 activation in Treg cells subjected to a selective ablation of SOCS1, a key negative regulator of Stat1 phosphorylation downstream of 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/c0e85e7825cf0dcc1fd7601e72132f6633ae2167

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Citations in the corpus

MicroRNAs in stress signaling and human disease (2012, background): “For example, haploinsufficency of the miR146a target Stat1 rescues the autoimmune pathology that arises in miR-146a knockout mice, implicating a central role for this target in this miRNA deletion phenotype (Lu et al., 2010).”
Phenotypic and functional specialization of FOXP3+ regulatory T cells (2011, background): “However, although IFNγ-induced signalling within T Reg cells may be beneficial for the differentiation of functionally specialized T-bet + T Reg cells, excessive STAT1 activation can have a deleterious effect on T Reg cell function, resulting in excessive T H 1 cell activity and inflammatory dis”
Metazoan MicroRNAs (2018, background): “miR-146 (2) miR-146a Hyperresponsive macrophages, exaggerated inflammatory response, and myeloid cell proliferation; eventual autoimmune disorders, exhaustion of hematopoietic stem cells, and hematopoietic neoplasms (Lu et al., 2010; Boldin et al., 2011; Zhao et al., 2013); altered pathology in five”
The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ (2011, neutral): “Also, miR-146a suppresses regulatory T cell functio”
microRNA regulation of inflammatory responses. (2012, background): “Our recent unpublished data also suggest that miR-146a is expressed in CD4+ and CD8+ effector T cells and functions to control the resolution of antigen-specific T cell responses by regulating NF-κB activation (L. Yang, M. Boldin, Y. Yu, C. Liu, C.-K. Ea, and D. Baltimore, unpublished observations).”
MicroRNAs in development and disease. (2011, background): “A recent report shows that, in this case, miR-146a is the miRNA responsible for T-reg cells’ suppressor function (388).”
miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice (2011, background): “Further studies will be required to test whether this T effector defect is cell autonomous or is actually a result of a defective function of regulatory T cells observed in miR-146a–null mice (Lu et al., 2010).”
Follicular Helper T Cells. (2016, background): “In addition to having effects on early activation through the same pathway (102), in CD4+ T cells, miR-146a also targets STAT1, thus enhancing Treg function (103).”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, background): “Similarly, excessive Stat1 activation in SOCS1deficient Treg cells also leads to dysregulated Th1 pathology (171).”