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      Age-Related Dynamics of Circulating Innate Lymphoid Cells in an African Population

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          Abstract

          Innate lymphoid cell (ILC) lineages mirror those of CD4+ T helper cell subsets, producing type 1, 2 and 3 cytokines respectively. Studies in adult human populations have shown contributions of non-cytotoxic ILC to immune regulation or pathogenesis in a wide range of diseases and have prompted investigations of potential functional redundancy between ILC and T helper cell compartments in neonates and children. To investigate the potential for ILC to contribute to immune responses across the human lifespan, we examined the numbers and frequencies of peripheral blood ILC subsets in a cohort of Gambians aged between 5 and 73 years of age. ILC2 were the most abundant peripheral blood ILC subset in this Gambian cohort, while ILC1 were the rarest at all ages. Moreover, the frequency of ILC1s (as a proportion of all lymphocytes) was remarkably stable over the life course whereas ILC3 cell frequencies and absolute numbers declined steadily across the life course and ILC2 frequencies and absolute numbers declined from childhood until the age of approx. 30 years of age. Age-related reductions in ILC2 cell numbers appeared to be partially offset by increasing numbers of total and GATA3+ central memory (CD45RA-CCR7+) CD4+ T cells, although there was also a gradual decline in numbers of total and GATA3+ effector memory (CD45RA-CCR7-) CD4+ T cells. Despite reduced overall abundance of ILC2 cells, we observed a coincident increase in the proportion of CD117+ ILC2, indicating potential for age-related adaptation of these cells in childhood and early adulthood. While both CD117+ and CD117- ILC2 cells produced IL-13, these responses occurred predominantly within CD117- cells. Furthermore, comparison of ILC frequencies between aged-matched Gambian and UK young adults (25–29 years) revealed an overall higher proportion of ILC1 and ILC2, but not ILC3 in Gambians. Thus, these data indicate ongoing age-related changes in ILC2 cells throughout life, which retain the capacity to differentiate into potent type 2 cytokine producing cells, consistent with an ongoing role in immune modulation.

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          Most cited references30

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          The biology of innate lymphoid cells.

          The innate immune system is composed of a diverse array of evolutionarily ancient haematopoietic cell types, including dendritic cells, monocytes, macrophages and granulocytes. These cell populations collaborate with each other, with the adaptive immune system and with non-haematopoietic cells to promote immunity, inflammation and tissue repair. Innate lymphoid cells are the most recently identified constituents of the innate immune system and have been the focus of intense investigation over the past five years. We summarize the studies that formally identified innate lymphoid cells and highlight their emerging roles in controlling tissue homeostasis in the context of infection, chronic inflammation, metabolic disease and cancer.
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            Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency.

            Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.
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              Tissue signals imprint ILC2 identity with anticipatory function

              Group 2 innate lymphoid cells (ILC2s) are distributed systemically and produce type 2 cytokines in response to a variety of stimuli, including the epithelial cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP). Transcriptional profiling of ILC2s from different tissues, however, grouped ILC2s according to their tissue of origin, even in the setting of combined IL-25, IL-33R and TSLPR-deficiency. Single-cell profiling confirmed a tissue-organizing transcriptome and identified ILC2 subsets expressing distinct activating receptors, including the major subset of skin ILC2s, which were activated preferentially by IL-18. Tissue ILC2 subsets were unaltered in number and expression in germ-free mice, suggesting that endogenous, tissue-derived signals drive the maturation of ILC2 subsets by controlling expression of distinct patterns of activating receptors, thus anticipating tissue-specific perturbations occurring later in life.
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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
                02 December 2020
                2020
                : 11
                : 594107
                Affiliations
                [1] 1 Department of Infection Biology, London School of Hygiene and Tropical Medicine , London, United Kingdom
                [2] 2 Vaccines & Immunity Theme, Infant Immunology, MRC Unit The Gambia at London School of Hygiene and Tropical Medicine , Fajara, Gambia
                [3] 3 Nuffield Department of Medicine, University of Oxford , Oxford, United Kingdom
                [4] 4 Division of Infection and Immunity, University College London , London, United Kingdom
                [5] 5 Nutrition Theme, MRC International Group, MRC Unit The Gambia at London School of Hygiene and Tropical Medicine , Keneba, Gambia
                [6] 6 Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine , London, United Kingdom
                [7] 7 Women & Children’s Health, Kings College London , London, United Kingdom
                [8] 8 Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh , Edinburgh, United Kingdom
                Author notes

                Edited by: Lutz Walter, Deutsches Primatenzentrum, Germany

                Reviewed by: Markus Uhrberg, Heinrich Heine University of Düsseldorf, Germany; Salim Iqbal Khakoo, University of Southampton, United Kingdom

                *Correspondence: Martin R. Goodier, martin.goodier@ 123456lshtm.ac.uk

                This article was submitted to NK and Innate Lymphoid Cell Biology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.594107
                7738635
                33343571
                cf590837-ca94-4cfc-ae7d-c97a855e428d
                Copyright © 2020 Darboe, Nielsen, Wolf, Wildfire, Danso, Sonko, Bottomley, Moore, Riley and Goodier

                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.

                History
                : 12 August 2020
                : 28 October 2020
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 30, Pages: 11, Words: 5169
                Funding
                Funded by: Medical Research Council 10.13039/501100000265
                Award ID: G1000808
                Funded by: Department for International Development, UK Government 10.13039/501100000278
                Award ID: G1000808
                Categories
                Immunology
                Original Research

                Immunology
                innate lymphoid cells,age,cd117,il-13,memory cd4+ t cells,gambia
                Immunology
                innate lymphoid cells, age, cd117, il-13, memory cd4+ t cells, gambia

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