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

Zheng, Qiwen; Zhou, Li; Mi, Qing Sheng

doi:10.4049/jimmunol.1103342

Cited by 69 publications

(70 citation statements)

References 59 publications

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“…Up to now, miR-150, miR-155, miR-181ab, and Let-7 were shown to play a role in iNKT cell development (9)(10)(11)(12)(13)(14). Their depletion from iNKT cells results in defects that partially recapitulate those observed in Dicer KO animals and affects the specific maturation stage at which each miRNA is expressed.…”

Section: Discussionmentioning

confidence: 72%

“…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).…”

mentioning

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).…”

mentioning

confidence: 99%

“…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). miR-155 is expressed by stage 1-2 iNKT cells and down-regulated at Significance CD1d-restricted invariant natural killer T (iNKT) cells are innate-like T lymphocytes that play fundamental roles in cancer, autoimmunity, and infections.…”

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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).…”

mentioning

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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Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

mentioning

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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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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AKT Isoforms in the Immune Response in Cancer

Ahmad

Somanath

2022

Current Topics in Microbiology and Immunology

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

Cited by 69 publications

References 59 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

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

AKT Isoforms in the Immune Response in Cancer

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