The Ligase PIAS1 Restricts Natural Regulatory T Cell Differentiation by Epigenetic Repression

Liu, Bin; Tahk, Samuel; Yee, Kathleen M.; Fan, Guoping; Shuai, Ke

doi:10.1126/science.1193787

Cited by 98 publications

(102 citation statements)

References 30 publications

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“…Thus, we suggest here a role for PIAS3 as a regulator of Th17 subset development and function. In this regard, it is interesting that a related E3 SUMO ligase, PIAS1, recently has been demonstrated to be a critical factor involved in the regulation and accessibility of the Foxp3 locus influencing Treg development, also with strong implications for the pathogenesis of EAE (40).…”

Section: Discussionmentioning

confidence: 99%

microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination

Mycko

Cichalewska²,

Machlańska³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

176

143

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MicroRNAs (miRNAs) are an emerging group of short, noncoding RNAs that play an important role in regulating expression of classical genes. Thus far little is known about their role in autoimmune demyelination. In this study, we analyzed changes in the miRNA profile in CD4 + T cells that occurred during the recognition of the myelin autoantigen, MOG . We found that, both in vivo and in vitro, myelin antigen stimulation resulted in significant up-regulation of miR-301a, miR-21, and miR-155. Furthermore, these three miRNAs were overexpressed in T cells infiltrating the CNS in animals with experimental autoimmune encephalomyelitis. Use of specific miRNA antagonists, antagomirs, revealed that miR-301a contributed to the development of the T-helper type 17 subset via targeting the IL-6/23-STAT3 pathway. This contribution appeared to be mediated by the miR-301a effect on the expression of the PIAS3, a potent inhibitor of the STAT3 pathway. Manipulation of miR-301a levels or PIAS3 expression in myelin-specific CD4 + T cells led to significant changes in the severity of experimental autoimmune encephalomyelitis. Thus, we have identified a role of miR-301a in regulating the function of myelinreactive T-helper type 17 cells, supporting a role for miR-301a and PIAS3 as candidates for therapeutic targets for controlling of autoimmune demyelination.M ultiple sclerosis (MS) is an organ-specific autoimmune disease manifested by chronic inflammatory demyelination of the CNS. CD4 + T-cell-mediated autoimmunity, with a critical role of a putative myelin autoantigen, has long been accepted as one of the most important aspects of MS pathogenesis, especially for the early initiation of disease (1). This understanding has been particularly complemented by the research on the MS animal model, experimental autoimmune encephalomyelitis (EAE). T-helper type 1 (Th1) cells, characterized by the expression of the transcription factor T-bet and the production of IFN-γ, originally were considered the major effector T-helper cells that mediate the pathogenesis of autoimmune demyelination (2). More recently another subset of T-helper cells, Th17, characterized by expression of the transcription factors retinoic acid receptor-related orphan receptor alpha (ROR-α) and retinoic acid receptor-related orphan receptor gamma t (ROR-γt) and by the production of IL-17, has been considered pivotal for the propagation of autoimmune demyelination (3). Mice with impaired numbers or function of Th17 cells, particularly mice deficient in the cytokines IL-6 or IL-23, are largely resistant to EAE (4-6). However, precise mechanisms governing the development and function of Th17 cells resulting in autoimmune demyelination are still unclear. Thus, Th17-targeting therapeutic approaches for MS have not yet been established.MicroRNAs (miRNAs) have begun to emerge as an important component in the differentiation and function of cells involved in the immune response. miRNAs operate as noncoding RNA molecules ∼22 nt in length that are processed from larger transcripts o...

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Section: Discussionmentioning

confidence: 99%

microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination

Mycko

Cichalewska²,

Machlańska³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

176

143

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“…Thus, whereas DNA methyltransferase 3a (DNMT3a) deficiency does not affect the initial polarization of T H 1, T H 2, T H 17 or pT Reg cell subsets, following restimulation with IL-12 (that is, T H 1 cell-polarizing conditions), all subsets produce IFNγ 147 . Disrupting the recruitment of DNMT3A to the Foxp3 locus leads to the inappropriate induction of FOXP3 expression in T helper cells 148 .…”

Section: Dna Accessibility By Modification Of Dna and Histonesmentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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“…79 More recently, the SUMO E3 ligase PIAS1 has been shown to recruit DNA methylases and heterochromatin protein 1 to reduce Foxp3 promoter accessibility. 80 The elucidation of how Treg cell instability relates to the known properties of epigenetic regulation of the Foxp3 locus could therefore provide important insights into the reversibility of 'ex-Foxp3' T cells. Additionally, any future therapies involving the use of the ex vivo expanded and infused Treg cells in humans 42,43 may require further testing of their epigenetic state to ensure that the most stable Treg cells are utilized.…”

Section: Epigenetic and Transcriptional Regulation Of Foxp3mentioning

confidence: 99%

Molecular mechanisms underlying the regulation and functional plasticity of FOXP3+ regulatory T cells

et al. 2011

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CD4þ CD25 þ regulatory T (Treg) cells engage in the maintenance of immunological self-tolerance and homeostasis by limiting aberrant or excessive inflammation. The transcription factor forkhead box P3 (FOXP3) is critical for the development and function of Treg cells. The differentiation of the Treg cell lineage is not terminal, as developmental and functional plasticity occur through the sensing of inflammatory signals in the periphery. Here, we review the recent progress in our understanding of the molecular mechanisms underlying the regulation and functional plasticity of CD4 þ CD25 þ FOXP3 þ Treg cells, through the perturbation of FOXP3 and its complex at a transcriptional, translational and post-translational level.

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The Ligase PIAS1 Restricts Natural Regulatory T Cell Differentiation by Epigenetic Repression

Cited by 98 publications

References 30 publications

microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination

microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

Molecular mechanisms underlying the regulation and functional plasticity of FOXP3+ regulatory T cells

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