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Hippo signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE144778 | GEO | 2020/04/07

REPOSITORIES: GEO

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Hippo/Mst signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions.

Project description:Invariant natural killer T (iNKT) cells acquire effector functions during development by mechanisms that remain poorly understood. Here, we show that the Hippo kinases Mst1 and Mst2 act as molecular rheostats for the terminal maturation and effector differentiation programs of iNKT cells. Loss of Mst1 alone or together with Mst2 impedes iNKT cell development, associated with defective IL-15-dependent cell survival. Mechanistically, Mst1 enforces iNKT cellular and transcriptional quiescence associated with maturation and commitment to iNKT1 cells by suppressing proliferation and Opa1-related mitochondrial metabolism that are dynamically regulated during iNKT cell development. Furthermore, Mst1 shapes the reciprocal fate decisions between iNKT1 and iNKT17 effector cells, which respectively depend upon mitochondrial dynamics and ICOS-mTORC2 signaling. Collectively, these findings establish Mst1 as a crucial regulator of mitochondrial homeostasis and quiescence in iNKT cell development and effector lineage differentiation and highlight that establishment of quiescence programs underlies iNKT cell development and effector maturation.

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Hippo signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions [ClariomS]

Project description:Hippo kinases Mst1 and Mst2 act as molecular rheostats for the terminal maturation and effector differentiation programs of iNKT cells. Loss of Mst1 alone or with Mst2 impedes iNKT cell development, associated with defective IL-15-dependent cell survival

2020-04-18 | GSE144776 | GEO

Hippo signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions [MoGene-2_0]

Project description:Hippo kinases Mst1 and Mst2 act as molecular rheostats for the terminal maturation and effector differentiation programs of iNKT cells. iNKT developmental stages 1, 2, and 3 (S1, S2, S3) were sorted from the thymus of WT (n = 3) and Cd4CreMst1fl/fl (n = 3) mice

2020-04-07 | GSE130043 | GEO

Hippo signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions

Project description:Hippo signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions

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Hippo signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions [ClariomS]

Project description:Hippo signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions [ClariomS]

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Hippo signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions [MoGene-2_0]

Project description:Hippo signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions [MoGene-2_0]

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iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions.

Project description:Terminal maturation of invariant NKT (iNKT) cells from stage 2 (CD44+NK1.1-) to stage 3 (CD44+NK1.1+) is accompanied by a functional acquisition of a predominant IFN-?-producing (iNKT-1) phenotype; however, some cells develop into IL-17-producing iNKT (iNKT-17) cells. iNKT-17 cells are rare and restricted to a CD44+NK1.1- lineage. It is unclear how iNKT terminal maturation is regulated and what factors mediate the predominance of iNKT-1 compared with iNKT-17. The tumor suppressor tuberous sclerosis 1 (TSC1) is an important negative regulator of mTOR signaling, which regulates T cell differentiation, function, and trafficking. Here, we determined that mice lacking TSC1 exhibit a developmental block of iNKT differentiation at stage 2 and skew from a predominantly iNKT-1 population toward a predominantly iNKT-17 population, leading to enhanced airway hypersensitivity. Evaluation of purified iNKT cells revealed that TSC1 promotes T-bet, which regulates iNKT maturation, but downregulates ICOS expression in iNKT cells by inhibiting mTOR complex 1 (mTORC1). Furthermore, mice lacking T-bet exhibited both a terminal maturation defect of iNKT cells and a predominance of iNKT-17 cells, and increased ICOS expression was required for the predominance of iNKT-17 cells in the population of TSC1-deficient iNKT cells. Our data indicate that TSC1-dependent control of mTORC1 is crucial for terminal iNKT maturation and effector lineage decisions, resulting in the predominance of iNKT-1 cells.

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PDCD5 regulates iNKT cell terminal maturation and iNKT1 fate decision.

Project description:Invariant natural killer T1 (iNKT1) cells are characterized by the preferential expression of T-box transcription factor T-bet (encoded by Tbx21) and the production of cytokine IFN-γ, but the relationship between the developmental process and iNKT1 lineage diversification in the thymus remains elusive. We report in the present study a crucial role of programmed cell death 5 (PDCD5) in iNKT cell terminal maturation and iNKT1 fate determination. Mice with T cell-specific deletion of PDCD5 had decreased numbers of thymic and peripheral iNKT cells with a predominantly immature phenotype and defects in response to α-galactosylceramide. Loss of PDCD5 also selectively abolished the iNKT1 lineage by reducing T-bet expression in iNKT cells at an early thymic developmental stage (before CD44 upregulation). We further demonstrated that TOX2, one of the high mobility group proteins that was highly expressed in iNKT cells at stage 1 and could be stabilized by PDCD5, promoted the permissive histone H3K4me3 modification in the promoter region of Tbx21. These data indicate a pivotal and unique role of PDCD5/TOX2 in iNKT1 lineage determination. They also suggest that the fate of iNKT1 may be programmed at the developmental stage of iNKT cells in the thymus.

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Quantifying the Landscape and Transition Paths for Proliferation-Quiescence Fate Decisions.

Project description:The cell cycle, essential for biological functions, experiences delicate spatiotemporal regulation. The transition between G1 and S phase, which is called the proliferation-quiescence decision, is critical to the cell cycle. However, the stability and underlying stochastic dynamical mechanisms of the proliferation-quiescence decision have not been fully understood. To quantify the process of the proliferation-quiescence decision, we constructed its underlying landscape based on the relevant gene regulatory network. We identified three attractors on the landscape corresponding to the G0, G1, and S phases, individually, which are supported by single-cell data. By calculating the transition path, which quantifies the potential barrier, we built expression profiles in temporal order for key regulators in different transitions. We propose that the two saddle points on the landscape characterize restriction point (RP) and G1/S checkpoint, respectively, which provides quantitative and physical explanations for the mechanisms of Rb governing the RP while p21 controlling the G1/S checkpoint. We found that Emi1 inhibits the transition from G0 to G1, while Emi1 in a suitable range facilitates the transition from G1 to S. These results are partially consistent with previous studies, which also suggested new roles of Emi1 in the cell cycle. By global sensitivity analysis, we identified some critical regulatory factors influencing the proliferation-quiescence decision. Our work provides a global view of the stochasticity and dynamics in the proliferation-quiescence decision of the cell cycle.

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Extrinsic allospecific signals of hematopoietic origin dictate iNKT cell lineage-fate decisions during development.

Project description:Invariant NKT (iNKT) cells are critical to the maintenance of tolerance toward alloantigens encountered during postnatal life pointing to the existence of a process for self-education. However, the impact of developmentally encountered alloantigens in shaping the phenotype and function of iNKT cells has not been described. To better understand this process, the current report examined naïve iNKT cells as they matured in an allogeneic environment. Following the prenatal transfer of fetal hematopoietic cells between age-matched allogeneic murine fetuses, cell-extrinsic signals appeared to dictate allospecific patterns of Ly49 receptor expression and lineage diversity in developing iNKT cells. Regulation for this process arose from cells of hematopoietic origin requiring only rare exposure to facilitate broad changes in developing iNKT cells. These findings highlight surprisingly asymmetric allospecific alterations in iNKT cells as they develop and mature in an allogeneic environment and establish a new paradigm for study of the self-education of iNKT cells.

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