Intrauterine growth restriction and prematurity influence regulatory T cell development in newborns

Mukhopadhyay, Dhriti; Weaver, Laura; Tobin, Richard P.; Henderson, Stephanie; Beeram, Madhava R.; Newell‐Rogers, M. Karen; Perger, Lena

doi:10.1016/j.jpedsurg.2014.02.055

Cited by 23 publications

(18 citation statements)

References 25 publications

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“…However, we have not investigated the suppressive function of these increased T regs during the early neonatal period because of the limited number of cells available. Previous studies revealed that T regs in CB from preterm infants have lower activity than those in CB from term infants and adult PB [36][37][38]. The difference in the function of T reg due to prematurity may affect the frequency of T regs and its subpopulations during the neonatal period.…”

Section: Discussionmentioning

confidence: 99%

Significant augmentation of regulatory T cell numbers occurs during the early neonatal period

Hayakawa

Ohno

Okada

et al. 2017

Clinical and Experimental Immunology

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Regulatory T cells (T ) control immune responses by suppressing various inflammatory cells. T in newborn babies may play an important role in preventing excessive immune responses during their environmental change. We examined the number and phenotype of T during the neonatal period in 49 newborn babies. T were characterized by flow cytometry using cord blood (CB) and peripheral blood (PB) from the early (7-8 days after birth) and late (2-4 weeks after birth) neonatal periods. CD4 forkhead box protein 3 (FoxP3 ) T cells were classified into resting T (CD45RA FoxP3 ), activated T (CD45RA FoxP3 ) and newly activated T cells (CD45RA FoxP3 ). Compared with CB and PB during the late neonatal period, the percentage of T and all T subpopulations in the CD4 lymphocyte population were increased significantly during the early neonatal period. Furthermore, the proportion and absolute number of activated T were increased markedly compared with other T subpopulations, such as resting T and newly activated T cells (non-T ), in the early neonatal period. Increased T concomitantly expressed the suppressive molecule cytotoxic T lymphocyte antigen-4 (CTLA-4). The up-regulated expression of chemokine receptor 4 (CCR4) and down-regulated expression of CCR7 were also observed in expanded T . When cord blood cells were cultured in vitro with CD3 monoclonal antibodies (mAb) for 5 days, CD4 CD45RA FoxP3 cells were increased significantly during the culture. Thus, the presence of increased activated T in early neonates may play an important role in immunological regulation by suppressing excessive T cell activation caused by the immediate exposure to ubiquitous antigens after birth.

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Section: Discussionmentioning

confidence: 99%

Significant augmentation of regulatory T cell numbers occurs during the early neonatal period

Hayakawa

Ohno

Okada

et al. 2017

Clinical and Experimental Immunology

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“…We previously showed that nTreg make up the majority of FOXP3 positive CD4 + T cells at birth . Studies suggest that birth‐related factors, including gestation and mode of delivery, influence the proportion of Treg in cord blood but the methods used to identify Treg vary, and results have been conflicting . Importantly, few studies have considered the impact of perinatal factors on the relationship between cord blood immune phenotype and allergic disease.…”

Section: Introductionmentioning

confidence: 99%

Naïve regulatory T cells in infancy: Associations with perinatal factors and development of food allergy

Collier

Ponsonby

O’Hely

et al. 2019

Allergy

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Background:In previous studies, deficits in regulatory T-cell (Treg) number and function at birth have been linked with subsequent allergic disease. However, longitudinal studies that account for relevant perinatal factors are required. The aim of this study was to investigate the relationship between perinatal factors, naïve Treg (nTreg) over the first postnatal year and development of food allergy. Methods:In a birth cohort (n = 1074), the proportion of nTreg in the CD4 + T-cell compartment was measured by flow cytometry at birth (n = 463), 6 (n = 600) and 12 (n = 675) months. IgE-mediated food allergy was determined by food challenge at 1 year. Associations between perinatal factors (gestation, labour, sex, birth size), nTreg at each time point and food allergy at 1 year were examined by linear regression. Results:A higher proportion of nTreg at birth, larger birth size and male sex was each associated with higher nTreg in infancy. Exposure to labour, as compared to delivery by prelabour Caesarean section, was associated with a transient decrease nTreg.Infants that developed food allergy had decreased nTreg at birth, and the labour-associated decrease in nTreg at birth was more evident among infants with subsequent food allergy. Mode of birth was not associated with risk of food allergy, and there was no evidence that nTreg at either 6 or 12 months were related to food allergy. Conclusion:The proportion of nTreg at birth is a major determinant of the proportion present throughout infancy, highlighting the importance of prenatal immune development. Exposure to the inflammatory stimulus of labour appears to reveal differences in immune function among infants at risk of food allergy. K E Y W O R D S food allergy, naïve regulatory T cells, perinatal factors | 1761 COLLIER Et aL. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Collier F, Ponsonby A-L, O'Hely M, et al. Naïve regulatory T cells in infancy: Associations with perinatal factors and development of food allergy. Allergy.

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“…Recent studies have demonstrated that CD3 + T cells play an important role in obesity and other inflammatory diseases by inducing inflammation and promoting insulin resistance via accumulation of inflammatory macrophages in adipose tissue [14]. IUGR is also associated with a decrease in the number of circulating regulatory T cells (Tregs) in cord blood [15] and a decrease in subpopulations responsible for regulating inflammation, including CD3 + cells in uterine decidua [16]. Thus, exposure to inflammation during fetal life may link growth restriction with subsequent development of type 2 diabetes [17].…”

Section: Introductionmentioning

confidence: 99%

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

et al. 2016

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Aims/hypothesis Intrauterine growth restriction (IUGR) is associated with increased susceptibility to obesity, metabolic syndrome and type 2 diabetes. Although the mechanisms underlying the developmental origins of metabolic disease are poorly understood, evidence suggests that epigenomic alterations play a critical role. We sought to identify changes in DNA methylation patterns that are associated with IUGR in CD3 + T cells purified from umbilical cord blood obtained from male newborns who were appropriate for gestational age (AGA) or who had been exposed to IUGR. Methods CD3 + T cells were isolated from cord blood obtained from IUGR and AGA infants. The genome-wide methylation profile in eight AGA and seven IUGR samples was determined using the HELP tagging assay. Validation analysis using targeted bisulfite sequencing and bisulfite massARRAY was performed on the original cohort as well as biological replicates consisting of two AGA and four IUGR infants. The Segway algorithm was used to identify methylation changes within regulatory regions of the genome. Results A global shift towards hypermethylation in IUGR was seen compared with AGA (89.8% of 4,425 differentially methylated loci), targeted to regulatory regions of the genome, specifically promoters and enhancers. Pathway analysis identified dysregulation of pathways involved in metabolic disease (type 2 diabetes mellitus, insulin signalling, mitogen-activated protein kinase signalling) and T cell development, regulation and activation (T cell receptor signalling), as well as transcription factors (TCF3, LEF1 and NFATC) that regulate T cells. Furthermore, bump-hunting analysis revealed differentially methylated regions in PRDM16 and HLA-DPB1, genes important for adipose tissue differentiation, stem cell maintenance and function and T cell activation. Conclusions/interpretation Our findings suggest that the alterations in methylation patterns observed in IUGR CD3 + T cells may have functional consequences in targeted genes, regulatory regions and transcription factors. These may serve as biomarkers to identify those at 'high risk' for diminished attainment of full health potential who can benefit from early interventions.

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Intrauterine growth restriction and prematurity influence regulatory T cell development in newborns

Cited by 23 publications

References 25 publications

Significant augmentation of regulatory T cell numbers occurs during the early neonatal period

Significant augmentation of regulatory T cell numbers occurs during the early neonatal period

Naïve regulatory T cells in infancy: Associations with perinatal factors and development of food allergy

DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction

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