Abstract
Regulatory T cells (Treg) are integral for immune homeostasis. Here we demonstrate that canonical microRNAs (miRNAs) are required for Treg function because mice with DGCR8-deficient Treg cells spontaneously develop a scurfy-like disease. Using genetic lineage marking we show that absence of miRNAs leads to reduced FoxP3 expression in Treg cells in vivo. In vitro culture of purified DGCR8-deficient Treg leads to a loss of FoxP3 expression. We conclude that canonical miRNAs are essential to maintain stable FoxP3 expression and Treg function. Thus, signals interfering with miRNA homeostasis might contribute to autoimmune diseases.
Highlights
Immune regulation depends largely on regulatory T cells (Treg)
The microRNA miR-150 as a representative canonical miRNA was ablated in Treg (Fig. 1c) but not conventional CD4+ T cells (Fig. 1d)
The DROSHA - DGCR8 miRNA microprocessor complex is critical for the cleavage of primary miRNA transcripts and DGCR8 is thought to be specific for the processing of canonical miRNAs rather than other classes of nuclear RNAs 21] it remains controversial if and to what degree the microprocessor complex cleaves other RNAs including snoRNAs 26,27]
Summary
Immune regulation depends largely on regulatory T cells (Treg). These CD4+ helper T cells express the forkhead domain transcription factor FoxP3. Treg suppress proinflammatory cells using multiple mechanisms 2]. Treg do not produce Interleukin-2 (IL-2) or other lineage-specific proinflammatory cytokines such as Interferon-c (IFNc), Interleukin-17 (IL17) or IL-4. In the past few years, it has become commonly accepted that T cell lineage commitment is not as rigid as previously thought 3]. Multiple studies have challenged that Treg are stable under all circumstances 4,5,6,7,8,9] and the molecular program underlying Treg lineage commitment and maintenance of their stability is under intense investigation 10,11,12]. We have recently demonstrated that some Treg can lose FoxP3 expression and turn into pathogenic cells 5]. Understanding Treg stability is highly relevant for clinical trials involving therapeutic adoptive transfer of various kinds of Treg 13,14]
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