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      Increased Regulatory T Cells Precede the Development of Bronchopulmonary Dysplasia in Preterm Infants

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          Abstract

          Regulatory T cells (Tregs) are important for the ontogenetic control of immune activation and tissue damage in preterm infants. However, the role of Tregs for the development of bronchopulmonary dysplasia (BPD) is yet unclear. The aim of our study was to characterize CD4+ CD25+ forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants ( n = 382; 23 + 0 – 36 + 6 weeks of gestational age) with a focus on the first 28 days of life and the clinical endpoint BPD (supplemental oxygen for longer than 28 days of age). In a subgroup of preterm infants, we characterized the immunological phenotype of Tregs ( n = 23). The suppressive function of Tregs on CD4+CD25- T cells was compared in preterm, term and adult blood. We observed that extreme prematurity was associated with increased Treg frequencies which peaked in the second week of life. Independent of gestational age, increased Treg frequencies were noted to precede the development of BPD. The phenotype of preterm infant Tregs largely differed from adult Tregs and displayed an overall naïve Treg population (CD45RA+/HLA-DR-/Helios+), especially in the first days of life. On day 7 of life, a more activated Treg phenotype pattern (CCR6+, HLA-DR+, and Ki-67+) was observed. Tregs of preterm neonates had a higher immunosuppressive capacity against CD4+CD25- T cells compared to the Treg compartment of term neonates and adults. In conclusion, our data suggest increased frequencies and functions of Tregs in preterm neonates which display a distinct phenotype with dynamic changes in the first weeks of life. Hence, the continued abundance of Tregs may contribute to sustained inflammation preceding the development of BPD. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.

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          Most cited references 62

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          Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero.

          As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth.
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            Differentiation of effector CD4 T cell populations (*).

            CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.
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              Stereotypic Immune System Development in Newborn Children

              Summary Epidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 μL of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                30 September 2020
                2020
                : 11
                Affiliations
                1Department of Pediatrics, University of Lübeck , Lübeck, Germany
                2Department of Infectious Diseases and Microbiology, University of Lübeck , Lübeck, Germany
                3German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems , Lübeck, Germany
                4Department of Pediatrics, University Hospital Hamburg-Eppendorf , Hamburg, Germany
                5Department of Medical Biometry and Statistics, University of Lübeck , Lübeck, Germany
                6Research Group Medical Systems Biology, Christian-Albrechts-University Kiel , Kiel, Germany
                7University Children's Hospital, University of Würzburg , Würzburg, Germany
                8PRIMAL (Priming Immunity at the Beginning of Life) Consortium , Lübeck, Germany
                Author notes

                Edited by: Navin Kumar Verma, Nanyang Technological University, Singapore

                Reviewed by: Manolo Sambucci, Santa Lucia Foundation (IRCCS), Italy; Bhalchandra Mirlekar, University of North Carolina at Chapel Hill, United States

                *Correspondence: Julia Pagel julia.pagel@ 123456uksh.de

                This article was submitted to T Cell Biology, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2020.565257
                7554370
                Copyright © 2020 Pagel, Twisselmann, Rausch, Waschina, Hartz, Steinbeis, Olbertz, Nagel, Steinmetz, Faust, Demmert, Göpel, Herting, Rupp and Härtel.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 62, Pages: 12, Words: 9096
                Categories
                Immunology
                Original Research

                Immunology

                regulatory t cells, tregs, bronchopulmonary dysplasia, bpd, preterm infant, neonate, foxp3

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