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      Visualization and Identification of IL-7 Producing Cells in Reporter Mice

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          Abstract

          Interleukin-7 (IL-7) is required for lymphocyte development and homeostasis although the actual sites of IL-7 production have never been clearly identified. We produced a bacterial artificial chromosome (BAC) transgenic mouse expressing ECFP in the Il7 locus. The construct lacked a signal peptide and ECFP (enhanced cyan fluorescent protein ) accumulated inside IL-7-producing stromal cells in thoracic thymus, cervical thymus and bone marrow. In thymus, an extensive reticular network of IL-7-containing processes extended from cortical and medullary epithelial cells, closely contacting thymocytes. Central memory CD8 T cells, which require IL-7 and home to bone marrow, physically associated with IL-7-producing cells as we demonstrate by intravital imaging.

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          Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo.

          The naïve and memory T lymphocyte pools are maintained through poorly understood homeostatic mechanisms that may include signaling via cytokine receptors. We show that interleukin-7 (IL-7) plays multiple roles in regulating homeostasis of CD8+ T cells. We found that IL-7 was required for homeostatic expansion of naïve CD8+ and CD4+ T cells in lymphopenic hosts and for CD8+ T cell survival in normal hosts. In contrast, IL-7 was not necessary for growth of CD8+ T cells in response to a virus infection but was critical for generating T cell memory. Up-regulation of Bcl-2 in the absence of IL-7 signaling was impaired after activation in vivo. Homeostatic proliferation of memory cells was also partially dependent on IL-7. These results point to IL-7 as a pivotal cytokine in T cell homeostasis.
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            Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice

            Interleukin 7 (IL-7) stimulates the proliferation of B cell progenitors, thymocytes, and mature T cells through an interaction with a high affinity receptor (IL-7R) belonging to the hematopoietin receptor superfamily. We have further addressed the role of IL-7 and its receptor during B and T cell development by generating mice genetically deficient in IL-7R. Mutant mice display a profound reduction in thymic and peripheral lymphoid cellularity. Analyses of lymphoid progenitor populations in IL-7R-deficient mice define precisely those developmental stages affected by the mutation and reveal a critical role for IL-7R during early lymphoid development. Significantly, these studies indicate that the phase of thymocyte expansion occurring before the onset of T cell receptor gene rearrangement is critically dependent upon, and mediated by the high affinity receptor for IL-7.
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              Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine

              Interleukin (IL)-7 is a potent stimulus for immature T and B cells and, to a lesser extent, mature T cells. We have inactivated the IL-7 gene in the mouse germline by using gene-targeting techniques to further understand the biology of IL-7. Mutant mice were highly lymphopenic in the peripheral blood and lymphoid organs. Bone marrow B lymphopoiesis was blocked at the transition from pro-B to pre-B cells. Thymic cellularity was reduced 20-fold, but retained normal distribution of CD4 and CD8. Splenic T cellularity was reduced 10-fold. Splenic B cells, also reduced in number, showed an abnormal population of immature B cells in adult animals. The remaining splenic populations of lymphocytes showed normal responsiveness to mitogenic stimuli. These data show that proper T and B cell development is dependent on IL-7. The IL-7-deficient mice are the first example of single cytokine- deficient mice that exhibit severe lymphoid abnormalities.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2009
                10 November 2009
                : 4
                : 11
                : e7637
                Affiliations
                [1 ]Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institute of Health, Frederick, Maryland, United States of America
                [2 ]Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, United States of America
                [3 ]Laboratory Animal Science Program (LASP), Science Applications International Corporation (SAIC), Cancer Research Center, National Cancer Institute, Frederick, Maryland, United States of America
                [4 ]Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                [5 ]Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institute of Health, Frederick, Maryland, United States of America
                [6 ]The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
                [7 ]Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [8 ]Human Retrovirus Section, Vaccine Branch, Center for Cancer Research NCI, Frederick, Maryland, United States of America
                [9 ]Gene Expression Laboratory, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, United States of America
                [10 ]Department of Immunology, University of Washington, Seattle, Washington, United States of America
                New York University School of Medicine, United States of America
                Author notes

                Conceived and designed the experiments: RIM AVW DWM RNG NAJ NGC SKD. Performed the experiments: RIM SW SML MI MA LF ACW DJS JAH MM JC DN LRS AGF KR. Analyzed the data: RIM WQL MRA AGF SKD. Contributed reagents/materials/analysis tools: DHDG BER. Wrote the paper: RIM SKD.

                [¤a]

                Current address: Laboratory of Gene Therapy and Primary Immunodeficiency, San Raffaele Telethon Institute for Gene Therapy, HSR-TIGET, Milano, Italy,

                [¤b]

                Current address: Genentech, Inc., Department of Molecular Biology, South San Francisco, California, United States of America

                [¤c]

                Current address: Laboratory of Biological Imaging, Immunology Frontier Research Center, Osaka University, Osaka, Japan

                [¤d]

                Current address: Twinbrook Flow Cytometry Facility, Lockheed Martin Contractor, RTB/NIAID/NIH, Rockville, Maryland, United States of America

                [¤e]

                Current address: Department of Biology, University of Puerto Rico Recinto Mayaguez, Mayaguez, Puerto Rico

                [¤f]

                Current address: Institute of Molecular and Cell Biology, Proteos, Singapore

                Article
                09-PONE-RA-12143
                10.1371/journal.pone.0007637
                2770321
                19907640
                ce36775c-fbc3-4a7e-a3b3-9c2b5e7db749
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                : 7 August 2009
                : 22 September 2009
                Page count
                Pages: 14
                Categories
                Research Article
                Immunology
                Immunology/Leukocyte Development
                Immunology/Leukocyte Signaling and Gene Expression

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                Uncategorized

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