Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function

Pobezinsky, Leonid A; Etzensperger, Ruth; Jeurling, Susanna; Alag, Amala; Kadakia, Tejas; McCaughtry, Tom M.; Kimura, Motoko; Sharrow, Susan O.; Guinter, Terry I.; Feigenbaum, Lionel; Singer, Alfred

doi:10.1038/ni.3146

Cited by 131 publications

(155 citation statements)

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“…By either deletion or overexpression, miR-150, miR-155, miR-181ab, and Let-7 have so far been implicated in the regulation of iNKT cells development and maturation (9)(10)(11)(12)(13)(14). The effects of these miRNAs depend critically on their timing of expression throughout iNKT cell maturation, underscoring the critical context-dependent regulatory effects of these molecules (9)(10)(11)(12)(13)(14). miR-150 expression increases progressively from thymic iNKT cell stage 1 to stage 3. miR-150 depletion or overexpression results in a modest decrease of stage 3 cells, associated with an up-regulation or down-regulation, respectively, of the target c-Myb mRNA and increased apoptosis (9,10).…”

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confidence: 99%

“…The overall defects observed in Dicer KO iNKT cells are the combinatorial product of the lack of each single miRNA that is relevant for their development. By either deletion or overexpression, miR-150, miR-155, miR-181ab, and Let-7 have so far been implicated in the regulation of iNKT cells development and maturation (9)(10)(11)(12)(13)(14). The effects of these miRNAs depend critically on their timing of expression throughout iNKT cell maturation, underscoring the critical context-dependent regulatory effects of these molecules (9)(10)(11)(12)(13)(14).…”

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confidence: 99%

“…miR-181 depletion results in a dramatic reduction of iNKT cells between stage 0 and 1, increased TCR signaling threshold, impaired PTEN expression, and regulation of global metabolic fitness (12,13). Let-7 expression in thymic iNKT cells increases from stages 0-3 and plays a critical role in iNKT cell differentiation by down-regulating the expression of the PLZF master gene regulator, determining their full terminal effector and phenotypic maturation (14).…”

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confidence: 99%

“…The thymic iNKT cell developmental program critically depends upon microRNAs (miRNAs) (7)(8)(9)(10)(11)(12)(13)(14). Deletion of Dicer, the RNase enzyme required for the generation of mature miRNAs, at the thymic DP stage lead to a dramatic and selective reduction of iNKT cells, resulting from an almost complete differentiation block and increased cell death at stage 2 (7).…”

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confidence: 99%

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miR-17∼92 family clusters control iNKT cell ontogenesis via modulation of TGF-β signaling

Fedeli

Riba

Manteiga

et al. 2016

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

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Invariant natural killer T cells (iNKT) cells are T lymphocytes displaying innate effector functions, acquired through a distinct thymic developmental program regulated by microRNAs (miRNAs). Deleting miRNAs by Dicer ablation (Dicer KO) in thymocytes selectively impairs iNKT cell survival and functional differentiation. To unravel this miRNA-dependent program, we systemically identified transcripts that were differentially expressed between WT and Dicer KO iNKT cells at different differentiation stages and predicted to be targeted by the iNKT cell-specific miRNAs. TGF-β receptor II (TGF-βRII), critically implicated in iNKT cell differentiation, was found up-regulated in iNKT Dicer KO cells together with enhanced TGF-β signaling. miRNA members of the miR-17∼92 family clusters were predicted to target Tgfbr2 mRNA upon iNKT cell development. iNKT cells lacking all three miR-17∼92 family clusters (miR-17∼92, miR-106a∼363, miR-106b∼25) phenocopied both increased TGF-βRII expression and signaling, and defective effector differentiation, displayed by iNKT Dicer KO cells. Consistently, genetic ablation of TGF-β signaling in the absence of miRNAs rescued iNKT cell differentiation. These results elucidate the global impact of miRNAs on the iNKT cell developmental program and uncover the targeting of a lineage-specific cytokine signaling by miRNAs as a mechanism regulating innate-like T-cell development and effector differentiation.NKT cells | miRNA | TGF-β | development | CD1d

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confidence: 99%

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confidence: 99%

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miR-17∼92 family clusters control iNKT cell ontogenesis via modulation of TGF-β signaling

Fedeli

Riba

Manteiga

et al. 2016

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

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“…The miRNA let-7 is known mostly for its function in development (62,63) and some roles in immunity (64-67), including regulation of NKT cell development (68) and IL-6 expression (69), but it was not previously seen in regulation of MHC. To determine whether other MHC class I genes are potential targets for let-7, we analyzed several members of the human MHC gene family using TargetScan (35).…”

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The Minor MHC Class I Gene UDA of Ducks Is Regulated by Let-7 MicroRNA

Chan

Parks-Dely

Magor

et al. 2016

The Journal of Immunology

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In many nonmammalian vertebrates, the genomic organization of the MHC class I region leads to biased expression of a single classical MHC class I gene coevolving with TAP transporters, whereas class I genes are poorly expressed. This contrasts to the three codominantly expressed classical MHC class I genes in humans and mice. In a sequenced haplotype from White Pekin duck, Anas platyrhynchos, there is one predominantly expressed MHC class I, UAA, although they have five MHC class I genes in the complex, arranged TAP1-TAP2-UAA-UBA-UCA-UDA-UEA. The UAA gene, situated proximal to the TAP2 gene, is expressed at levels 10-fold greater than that of another expressed gene, UDA. Three duck MHC class I genes (UBA, UCA, and UEA) are predicted to be partially or completely inactivated by promoter defects, introduction of in-frame stop codon, or the lack of a polyadenylation signal. In this study, we confirm that UBA, UCA, and UEA are indeed inactivated through genetic defects at the promoter, whereas UAA and UDA have functionally equivalent promoters. To examine promoter accessibility, we performed bisulfite sequencing and show that none of the MHC class I promoters are inactivated by methylation. We determine that UDA is differentially regulated through its 3′ untranslated region. Namely, expression of UDA is downregulated by let-7 microRNA, whereas the predominantly expressed MHC class I UAA is not. Regulation of UDA by let-7 microRNA suggests that the lower expression level is maintained for its function in immunity.

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miR‐21 sustains CD28 signalling and low‐affinity T‐cell responses at the expense of self‐tolerance

et al. 2021

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Objective miR‐21 is highly expressed in iNKT and activated T cells, but its T‐cell autonomous functions are poorly defined. We sought to investigate the role of miR‐21 in the development and functions of T and iNKT cells, representing adaptive and innate‐like populations, respectively. Methods We studied mice with a conditional deletion of miR‐21 in all mature T lymphocytes. Results Thymic and peripheral T and iNKT compartments were normal in miR‐21 KO mice. Upon activation in vitro, miR‐21 depletion reduced T‐cell survival, TH17 polarisation and, remarkably, T‐ and iNKT cell ability to respond to low‐affinity antigens, without altering their response to high‐affinity ones. Mechanistically, miR‐21 sustained CD28‐dependent costimulation pathways required to lower the T‐cell activation threshold, inhibiting its repressors in a positive feedback circuit, in turn increasing T‐cell sensitivity to antigenic stimulation and survival. Upon immunisation with the low‐affinity self‐epitope MOG35–55, miR‐21 KO mice were indeed less susceptible than WT animals to the induction of experimental autoimmune encephalomyelitis, whereas they mounted normal T‐cell responses against high‐affinity viral epitopes generated upon lymphocytic choriomeningitis virus infection. Conclusion The induction of T‐cell responses to weak antigens (signal 1) depends on CD28 costimulation (signal 2). miR‐21 sustains CD28 costimulation, decreasing the T‐cell activation threshold and increasing their sensitivity to antigenic stimulation and survival, broadening the immune surveillance range. This occurs at the cost of unleashing autoimmunity, resulting from the recognition of weak self‐antigens by autoreactive immune responses. Thus, miR‐21 fine‐tunes T‐cell response and self‐/non‐self‐discrimination.

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Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function

Cited by 131 publications

References 47 publications

miR-17∼92 family clusters control iNKT cell ontogenesis via modulation of TGF-β signaling

miR-17∼92 family clusters control iNKT cell ontogenesis via modulation of TGF-β signaling

The Minor MHC Class I Gene UDA of Ducks Is Regulated by Let-7 MicroRNA

miR‐21 sustains CD28 signalling and low‐affinity T‐cell responses at the expense of self‐tolerance

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