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RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.

ABSTRACT: Successful pregnancies rely on adaptations within the mother¹, including marked changes within the immune system². It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy³. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK^4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T_reg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T_reg cells through RANK in a manner that depends on AIRE⁺ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T_reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T_reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T_reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T_reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T_reg cells during pregnancy, and expand the functional role of maternal T_reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.

SUBMITTER: Paolino M

PROVIDER: S-EPMC7116618 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.

Paolino Magdalena M Koglgruber Rubina R Cronin Shane J F SJF Uribesalgo Iris I Rauscher Esther E Harreiter Jürgen J Schuster Michael M Bancher-Todesca Dagmar D Pranjic Blanka B Novatchkova Maria M Fededa Juan P JP White Andrea J AJ Sigl Verena V Dekan Sabine S Penz Thomas T Bock Christoph C Kenner Lukas L Holländer Georg A GA Anderson Graham G Kautzky-Willer Alexandra A Penninger Josef M JM

Nature 20201223 7842

Successful pregnancies rely on adaptations within the mother1, including marked changes within the immune system2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic del ...[more]

PMID: 33361811

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Project description:BackgroundPre-pregnancy body mass index (BMI), gestational diabetes mellitus (GDM), and gestational weight gain (GWG) are interlinked and may play a complex role in fetal growth. We aimed to examine the relationship between pre-pregnancy BMI, GDM, GWG, and fetal growth outcomes and explore the contribution of GDM and GWG to the relationship between Pre-pregnancy obesity/overweight and large-for-gestational-age (LGA) in a prospective cohort.MethodsWe prospectively recruited women in the first trimester and having one-step GDM screened with a 75-g oral glucose tolerance test between 24 and 28 weeks of gestation (n = 802). Outcomes included LGA, small-for-gestational-age (SGA), and preterm birth. To assess the individual and cumulative associations between pre-pregnancy BMI, GDM, GWG, and these outcomes, we used multivariate logistic regression analysis. Furthermore, we employed structural equation modeling (SEM) to investigate the mediating role of GDM and excessive GWG in the correlation between pre-pregnancy overweight/obesity and LGA.ResultsPre-pregnancy obesity, GDM, and excessive GWG were all independently associated with increased odds of LGA. Inadequate GWG was associated with higher odds of preterm birth. Compared with women unexposed to pre-pregnancy overweight/obesity, GDM, or excessive GWG, women exposed any two conditions had higher odds for LGA (AOR 3.18, 95% CI 1.25-8.11) and women with coexistence of all had the highest odds for LGA (AOR 8.09, 95% CI 2.18-29.97). The mediation analysis showed that GDM explained 18.60% (p < 0.05) of the total effect of pre-pregnancy overweight/obesity on LGA, and GWG explained 17.44% (p < 0.05) of the total effect.ConclusionPre-pregnancy obesity/overweight, GDM, and excessive GWG are associated with higher odds of fetal growth disturbances as individual factors and when they co-exist. The effect of pre-pregnancy overweight/obesity on LGA is partially achieved through GDM and excessive GWG.

Project description:BackgroundMaternal gestational diabetes (GDM) is an established risk factor for large size at birth, but its influence on intrauterine fetal growth in different ethnic populations is less well understood. Here, we examine the joint associations of GDM and ethnicity with longitudinal fetal growth in South Asian and White European origin women.MethodsThis study included 10,705 singletons (4747 White European and 5958 South Asian) from a prospective cohort of women attending an antenatal clinic in Bradford, in the North of England. All women completed a 75-g oral glucose tolerance test at 26-28 weeks' gestation. Ultrasound measurements of fetal head circumference (HC), femur length (FL) abdominal circumference (AC), and estimated fetal weight (EFW), and corresponding anthropometric measurements at birth were used to derive fetal growth trajectories. Associations of GDM and ethnicity with these trajectories were assessed using multilevel fractional polynomial models.ResultsEight hundred thirty-two pregnancies (7.8%) were affected by GDM: 10.4% of South Asians and 4.4% of White Europeans. GDM was associated with a smaller fetal size in early pregnancy [differences (95% CI) in mean HC at 12 weeks and mean AC and EFW at 16 weeks comparing fetuses exposed to GDM to fetuses unexposed (reference) = - 1.8 mm (- 2.6; - 1.0), - 1.7 mm (- 2.5; - 0.9), and - 6 g (- 10; - 2)] and a greater fetal size from 24 weeks' gestation through to term [differences (95% CI) in mean HC, AC, and EFW comparing fetuses exposed to GDM to those unexposed = 0.9 mm (0.3; 1.4), 0.9 mm (0.2; 1.7), and 7 g (0; 13) at 24 weeks]. Associations of GDM with fetal growth were of similar magnitude in both ethnic groups. Growth trajectories, however, differed by ethnicity with South Asians being smaller than White Europeans irrespective of GDM status. Consequently, South Asian fetuses exposed to GDM were smaller across gestation than fetuses of White Europeans without GDM.ConclusionsIn both ethnic groups, GDM is associated with early fetal size deviations prior to GDM diagnosis, highlighting the need for novel strategies to diagnose pregnancy hyperglycemia earlier than current methods. Our findings also suggest that ethnic-specific fetal growth criteria are important in identifying hyperglycemia-associated pathological effects.

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RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.

Publications

RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.

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