Epigenetic Reduction in Invariant NKT Cells following In Utero Vitamin D Deficiency in Mice

Yu, Sanhong; Cantorna, Margherita T.

doi:10.4049/jimmunol.1002545

Cited by 71 publications

(87 citation statements)

References 38 publications

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“…In future studies it will be interesting to maintain mice born to vitamin D-deficient mothers for extended periods of time to determine the impact of this on adult health. Other studies using mice have shown that gestational vitamin D deficiency is associated with aberrant expression and function of immune cells in the offspring (51). Finally, data showed that births in Def mice were more likely to occur preterm (ϽE18) compared with Suff mice.…”

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confidence: 56%

Dietary Vitamin D Restriction in Pregnant Female Mice Is Associated With Maternal Hypertension and Altered Placental and Fetal Development

et al. 2013

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Epidemiology has linked vitamin D deficiency with preeclampsia in humans. We hypothesized that low vitamin D status in pregnant mice may lead to symptoms of preeclampsia. Female BL6 mice were raised on vitamin D-sufficient or -deficient diets from weeks 4 of age and then mated with vitamin D-sufficient BL6 males at week 8. The resulting pregnant mice were either allowed to deliver pups and monitored for blood pressure (BP) and weight of offspring or euthanized at day 14 or 18 of gestation (E14 or E18) for analysis of serum, placental/kidney tissues, and fetuses. At E14 serum concentrations of 25-hydroxyvitamin D (30.1 Ϯ 5.0 vs 1.8 Ϯ 0.6 ng/mL, P Ͻ .001) and 1,25-dihydroxyvitamin D (119.5 Ϯ 18.7 vs 37.4 Ϯ 5.1 pg/mL, P Ͻ .01) were higher in sufficient vs deficient pregnant mice. At E14 BP was significantly elevated in vitamin D-deficient pregnant mice relative to vitamin D-sufficient mice for both systolic BP (124.89 Ϯ 2.28 vs 105.34 Ϯ 3.61 mm Hg, P Ͻ .001) and mean arterial pressure (115.33 Ϯ 1.93 vs 89.33 Ϯ 5.02 mm Hg, P Ͻ .001). This elevation continued through pregnancy until 7 days postpartum (PP7) but returned to baseline by PP14. Analysis of maternal kidneys showed increased expression of mRNA for renin and the angiotensin II receptor (3-and 4-fold, respectively) in vitamin D-deficient vs -sufficient mice at E14. Histological analysis of E14 placentas from vitamin D-deficient mice showed decreased vascular diameter within the labyrinth region. E14 and E18 fetuses from vitamin D-deficient mice were larger than those from vitamin D-sufficient mothers. However, by PP14 pups from vitamin D-deficient mothers weighed significantly less than those from vitamin D-sufficient mothers. Resupplementation of vitamin D periconceptually partially reversed the effects of vitamin D deficiency. These data provide further evidence that low vitamin D status may predispose pregnant women to dysregulated placental development and elevated blood pressure. (Endocrinology 154: 2270 -2280, 2013) P reeclampsia, typically characterized by maternal hypertension, proteinuria, and a variation of other signs and symptoms, is a leading cause of preterm delivery. Preeclampsia complicates up to 10% of all pregnancies, 3% severely with potential life-threatening consequences (1). Impaired vitamin D status appears to be prevalent among pregnant women in general (2), and epidemiology suggests that there is a link between vitamin D insufficiency and preeclampsia (3-5). A longitudinal study of 697 pregnant women showed an increased incidence of preeclampsia with lower maternal vitamin D levels measured at 24 -26 weeks' gestation (6). Likewise, a retrospective analysis of

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confidence: 56%

Dietary Vitamin D Restriction in Pregnant Female Mice Is Associated With Maternal Hypertension and Altered Placental and Fetal Development

et al. 2013

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“…VDR is also required for iNKT cell development (11). Importantly, vitamin D deficiency during embryogenesis affects iNKT cell development (39). Alternatively, Med1 might interact with another iNKT cell master regulator RORγt.…”

Section: Discussionmentioning

confidence: 99%

“…Further studies are needed to elucidate the interplay between Med1 and VDR, and the potential VDRdependent regulation of T-bet. Because vitamin D deficiency has been implicated in autoimmune disease (39), the VDR/Mediator interaction is of potential therapeutic interest.…”

Section: Discussionmentioning

confidence: 99%

Essential role of Mediator subunit Med1 in invariant natural killer T-cell development

Yue

Ízcue

Borggrefe

2011

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

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CD1d-restricted invariant NKT (iNKT) cells are a unique lineage of T lymphocytes that regulate both innate and adaptive immunity. The Mediator complex forms the bridge between transcriptional activators and the general transcription machinery. Med1/ TRAP220 (also called DRIP205) is a key component of Mediator that interacts with ligand-bound hormone receptors, such as the vitamin D receptor. Here, we show that T-cell-specific Med1 deficiency results in a specific block in iNKT cell development but the development of conventional αβ T cells remains grossly normal. The defect is cell-intrinsic and depends neither on apoptosis, cellcycle control, nor on CD1d expression of CD4 + CD8 + double-positive thymocytes. Surprisingly, ectopic expression of a Vα14-Jα18 T-cell receptor transgene completely rescues the defect caused by Med1 deficiency. At the molecular level, thymic iNKT cells in Med1animals display reduced levels of IL-2Rβ and T-bet expression and could not complete terminal maturation. Thus, Med1 is essential for a complete intrathymic development of iNKT cells.

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“…As yet, there have been no studies to assess the impact of vitamin D on decidual NKT function and pregnancy outcome. However, in studies carried out in mice, variations in vitamin D status (maternal serum 25OHD) in utero have been shown to result in altered NKT cell function of the resulting offspring (Yu & Cantorna 2011). This clearly has important implications for the potential impact of maternal vitamin D status on child health in humans.…”

Section: Decidual/uterine Nk Cellsmentioning

confidence: 99%

Immunological role of vitamin D at the maternal–fetal interface

Tamblyn¹,

Hewison²,

Wagner³

et al. 2015

Journal of Endocrinology

146

104

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Epigenetic Reduction in Invariant NKT Cells following In Utero Vitamin D Deficiency in Mice

Cited by 71 publications

References 38 publications

Dietary Vitamin D Restriction in Pregnant Female Mice Is Associated With Maternal Hypertension and Altered Placental and Fetal Development

Dietary Vitamin D Restriction in Pregnant Female Mice Is Associated With Maternal Hypertension and Altered Placental and Fetal Development

Essential role of Mediator subunit Med1 in invariant natural killer T-cell development

Immunological role of vitamin D at the maternal–fetal interface

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