Flicr , a long noncoding RNA, modulates Foxp3 expression and autoimmunity

Abstract

A combination of transcription factors, enhancers, and epigenetic marks determines the expression of the key transcription factor FoxP3 in regulatory T cells (Tregs). Adding an additional layer of complexity, the long noncoding RNA (lncRNA) Flicr (Foxp3 long intergenic noncoding RNA) is a negative regulator that tunes Foxp3 expression, resulting in a subset of Tregs with twofold-to fivefoldlower levels of FoxP3 protein. The impact of Flicr is particularly marked in conditions of IL-2 deficiency, and, conversely, IL-2 represses Flicr expression. Flicr neighbors Foxp3 in mouse and human genomes, is specifically expressed in mature Tregs, and acts only in cis. It does not affect DNA methylation, but modifies chromatin accessibility in the conserved noncoding sequence 3 (CNS3)/Accessible region 5 (AR5) region of Foxp3. Like many lncRNAs, Flicr's molecular effects are subtle, but by curtailing Treg activity, Flicr markedly promotes autoimmune diabetes and, conversely, restrains antiviral responses. This mechanism of FoxP3 control may allow escape from dominant Treg control during infection or cancer, at the cost of heightened autoimmunity.autoimmunity | regulatory T cells | gene regulation | long noncoding RNA | Foxp3

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…Evidence of the impact of long noncoding RNAs in immune function is becoming clear,91, 92 and alterations in function can be identified in autoimmune and chronic inflammation samples which are linked to lncRNAs 93. The importance of lncRNA in Treg has been elegantly demonstrated for a lncRNA (Flicr) which subtly controls the expression of FOXP3 in mouse and human Treg 94. Interestingly, the impact of Flicr on FOXP3 expression is via interactions with conserved noncoding elements and loss of Flickr results in reduced expression of FOXP3.…”

“…93 The importance of lncRNA in Treg has been elegantly demonstrated for a lncRNA (Flicr) which subtly controls the expression of FOXP3 in mouse and human Treg. 94 Interestingly, the impact of Flicr on FOXP3 expression is via interactions with conserved noncoding elements and loss of Flickr results in reduced expression of FOXP3. This may be the prerequisite for transcriptional reprogramming of Treg under external cues such as from reduced IL2 signalling, reinforcing the model that plasticity can be induced by relatively small changes in transcriptional networks.…”

Memory regulatory T cells home to the lung and control influenza A virus infection

“…Tregs were initially discovered as a key immunoregulator of autoimmunity, maintaining self‐tolerance via suppressing autoreactive T cells that have escaped negative selection in thymus . Imbalance between Tregs and autoreactive T cells, impaired Treg proliferation capacity or defects in Treg suppressive function may therefore lead to the development of a variety of autoimmune diseases . In addition to the maintenance of immune tolerance to self‐antigens, Tregs are involved in modulating immune responses to acute microbial pathogens.…”

“…3,4 Imbalance between Tregs and autoreactive T cells, impaired Treg proliferation capacity or defects in Treg suppressive function may therefore lead to the development of a variety of autoimmune diseases. [5][6][7][8] In addition to the maintenance of immune tolerance to self-antigens, Tregs are involved in modulating immune responses to acute microbial pathogens. For example, during acute infection by respiratory syncytial virus and herpes simplex virus, Tregs are critical in limiting the infection-induced innate and adaptive immune responses and the corresponding tissue inflammation at the infection sites.…”

A guide to naming human non‐coding RNA genes

“…Cis regulation of a neighbouring protein coding locus, which can be either positive or negative regulation; e.g., TARID binds to the promoter of, and activates, the TCF21 gene (Arab et al, 2014); PLUT upregulates transcription of PDX1 by affecting local 3D chromatin structure (Akerman et al, 2017); FLICR represses FOXP3 transcription by modifying chromatin accessibility (Zemmour et al, 2017). 2…”