<i>Tie2cre</i>
            -induced inactivation of the miRNA-processing enzyme Dicer disrupts invariant NKT cell development

Zhou, Li; Seo, Kook Heon; He, Hong; Pacholczyk, Rafał; Meng, Dong; Li, Chang Gui; Xu, Jiean; She, Jin‐Xiong; Dong, Zheng; Mi, Qing Sheng

doi:10.1073/pnas.0811119106

Cited by 88 publications

(87 citation statements)

References 32 publications

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“…This phenomenon has been linked in particular to the loss of function of miRNA-deficient Tregs, and mice with either a general deficiency of miRNA or selective knockdown of miR-146a in Tregs displayed a fatal autoimmune disease (26)(27)(28)(29)(30). However, miRNA ablation in T cells also results in defects in natural killer T-cell development (31,32) and the differentiation of T-helper cells that may contribute independently to autoimmunity (25,33).…”

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.

177

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.

177

143

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“…One possible reason is that in their transferring experiments, four to five mice per group may not have enough power to detect a difference for this mild reduction, compared with the almost complete blocking of early iNKT cell development in the mice with miR-150 overexpression. Compared with iNKT cells in bone marrow-or thymus-specific total miRNA deletion mouse models (26)(27)(28), miR-150 deletion alone is unlikely accountable for the profound interruption of iNKT cell development, maturation, and function identified in those mice. This may suggest the potential involvement of multiple miRNAs or groups of miRNAs in iNKT cell developmental and functional regulation, which is also supported by our recent miRNA expression profiles of iNKT cells (Q.H.…”

Section: Discussionmentioning

confidence: 99%

“…Small microRNAs (miRNAs) are short noncoding RNAs (20-23 nt) that negatively regulate gene expression by inducing the degradation or translational repression of the target protein-coding mRNAs (25). Recently, our laboratory and another group found that deletion of Dicer, the RNase III enzyme essential for the processing of mature functional miRNAs, results in a profound interruption of iNKT cell development, maturation, and function (26)(27)(28). However, little insight has been made concerning the role of specific miRNAs in the development and function of iNKT cells.…”

mentioning

confidence: 99%

MicroRNA miR-150 Is Involved in Vα14 Invariant NKT Cell Development and Function

Zheng

Zhou

2012

The Journal of Immunology

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CD1d-restricted Vα14 invariant NKT (iNKT) cells play an important role in the regulation of diverse immune responses. MicroRNA-mediated RNA interference is emerging as a crucial regulatory mechanism in the control of iNKT cell differentiation and function. Yet, roles of specific microRNAs in the development and function of iNKT cells remain to be further addressed. In this study, we identified the gradually increased expression of microRNA-150 (miR-150) during the maturation of iNKT cells in thymus. Using miR-150 knockout (KO) mice, we found that miR-150 deletion resulted in an interruption of iNKT cell final maturation in both thymus and periphery. Upon activation, iNKT cells from miR-150KO mice showed significantly increased IFN-γ production compared with wild-type iNKT cells. Bone marrow-transferring experiments demonstrated the cell-intrinsic characteristics of iNKT cell maturation and functional defects in mice lacking miR-150. Furthermore, miR-150 target c-Myb was significantly upregulated in miR-150KO iNKT cells, which potentially contribute to iNKT cell defects in miR-150KO mice. Our data define a specific role of miR-150 in the development and function of iNKT cells.

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“…Previous studies have shown that global miRNA loss as a result of Dicer deficiency results in severe defects in iNKT cell development (Fedeli et al, 2009;Zhou et al, 2009;Seo et al, 2010). iNKT cells developing in the thymus initially acquire V14-J18 TCR rearrangement, and then downregulate CD24, and finally up-regulate CD44 and NK1.1 as the last maturation step (Godfrey et al, 2010).…”

Section: The Development Of Inkt Cells Is Impaired In Mir-150 Tg and mentioning

confidence: 99%

“…microRNAs (miRNAs) are noncoding RNAs, expressed from endogenous genes, which act on proteinencoding mRNAs, targeting them for translational repression or degradation (Bartel, 2004). Many miRNAs are expressed in a stage-and cell-specific fashion in the hematopoietic system (Kuchen et al, 2010), and emerging evidence suggests that they regulate lymphocyte differentiation and function (Muljo et al, 2005;Cobb et al, 2006;Koralov et al, 2008;Liston et al, 2008;Zhou et al, 2009;Fedeli et al, 2009). Deletion of the miRNA-processing enzymes Dicer or Dgcr8 leads to defects in NK cell activation, survival, and function during mouse cytomegalovirus infection (Bezman et al, 2010).…”

mentioning

confidence: 99%

miR-150 regulates the development of NK and iNKT cells

Bezman¹,

Chakraborty²,

Bender³

et al. 2011

J Cell Biol

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Tie2cre -induced inactivation of the miRNA-processing enzyme Dicer disrupts invariant NKT cell development

Abstract: T cell ͉ thymus ͉ galactosylceramide ͉ bone marrow

Cited by 88 publications

References 32 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

MicroRNA miR-150 Is Involved in Vα14 Invariant NKT Cell Development and Function

miR-150 regulates the development of NK and iNKT cells

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