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      Stereotypic Immune System Development in Newborn Children

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          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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          Highlights

          • Cord blood is not representative of postnatal immunity

          • Preterm and term children differ at birth but rapidly converge thereafter

          • Immune system development follows a stereotypic pattern early in life

          • Dynamic parameters imply microbial interactions during early immune development

          Abstract

          Longitudinal profiling of blood immune cells from 100 newborns provides a systemic view on the ontogeny of the human neonatal immune system.

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          Most cited references25

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          Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans.

          A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.
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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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              Global analyses of human immune variation reveal baseline predictors of postvaccination responses.

              A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination. Peripheral blood mononuclear cell transcriptomes, serum titers, cell subpopulation frequencies, and B cell responses were assessed in 63 individuals before and after vaccination and were used to develop a systematic framework to dissect inter- and intra-individual variation and build predictive models of postvaccination antibody responses. Strikingly, independent of age and pre-existing antibody titers, accurate models could be constructed using pre-perturbation cell populations alone, which were validated using independent baseline time points. Most of the parameters contributing to prediction delineated temporally stable baseline differences across individuals, raising the prospect of immune monitoring before intervention.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                23 August 2018
                23 August 2018
                : 174
                : 5
                : 1277-1292.e14
                Affiliations
                [1 ]Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, 17121 Solna, Sweden
                [2 ]Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14152 Solna, Sweden
                [3 ]Department of Neonatology, Karolinska University Hospital, 17176 Solna, Sweden
                [4 ]Science for Life Laboratory, School of Biotechnology, KTH, Royal Institute of Technology, 17121 Stockholm, Sweden
                Author notes
                []Corresponding author petter.brodin@ 123456ki.se
                [5]

                These authors contributed equally

                [6]

                Lead Contact

                Article
                S0092-8674(18)30848-1
                10.1016/j.cell.2018.06.045
                6108833
                30142345
                c796901e-df63-4fd8-af06-148d36e0333e
                © 2018 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 20 November 2017
                : 18 May 2018
                : 22 June 2018
                Categories
                Article

                Cell biology
                systems immunology,human immunology,mass cytometry,cytof,newborn immune systems,neonatology,immune variation,preterm birth,immune system development,neonate

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