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A Flicr of hope for autoimmunity

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Science Immunology  05 May 2017:
Vol. 2, Issue 11, eaan5142
DOI: 10.1126/sciimmunol.aan5142

Abstract

The long noncoding RNA Flicr modifies Foxp3 chromatin accessibility to reduce T regulatory cell differentiation and function.

Long noncoding RNAs (lncRNAs) represent a large fraction of the transcriptome; however, only about 10% of human lncRNAs have homologs in mice. Zemmour et al. describe a new lncRNA, Flicr (Foxp3 long intergenic noncoding RNA), which is conserved between humans and mice and is located in close proximity to the Foxp3 locus. Flicr expression is limited to T regulatory cells (Tregs) in the immune system and down-regulates Foxp3 expression, resulting in phenotypic instability and decreased Treg function. Murine Flicr was found in Tregs from all lymphoid tissues and expressed in mature CD25hi natural Tregs. However, Flicr expression was decreased in activated Tregs and absent in induced Tregs. Foxp3 expression was necessary but not sufficient for Flicr expression.

Flicr-deficient mice developed normally with expected Treg numbers in tissues; however, Flicr-deficient mice had more FoxP3hi Tregs and fewer FoxP3lo Tregs compared with wild-type mice. FoxP3 expression was similarly modulated in mixed chimeras and in in vitro studies using an RNA interference approach targeting Flicr in Tregs. Thus, Flicr directly influences FoxP3 expression in a subset of Tregs. To examine the effect of Flicr on FoxP3 stability, the authors cultured Tregs in limited interleukin-2 (IL-2). FoxP3lo Tregs were absent from Flicr-deficient cells as compared with controls, but IL-2 stabilized FoxP3 expression and decreased Flicr expression. Mechanistically, Flicr acted in cis on Foxp3, influencing chromatin accessibility rather than DNA methylation at the Foxp3 locus. In sum, IL-2 and Flicr play opposing roles with regard to FoxP3 stabilization. Zemmour et al. then examined the downstream effects of these Treg differences on autoimmunity. Flicr-deficient nonobese diabetic female mice had a decreased rate and incidence of diabetes compared with controls. Moreover, correlation data on insulitis and Tregs in the pancreas indicated that Flicr-deficient Tregs were more potent than wild-type Tregs in suppressing disease.

Thus, Flicr is a cis-acting negative regulator of Treg Foxp3 expression with modest effects at the molecular level that translate into pronounced effects on peripheral immune tolerance. Attenuation of Treg Foxp3 expression by Flicr may permit vigorous antiviral responses but also increases the propensity to develop autoimmune disease.

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