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      A Role for Thymic Stromal Lymphopoietin in CD4 + T Cell Development

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          Abstract

          Thymic stromal lymphopoietin (TSLP) signals via a receptor comprising the interleukin (IL)-7 receptor α chain and a distinctive subunit, TSLP receptor (TSLPR), which is most related to the common cytokine receptor γ chain, γ c. We have generated TSLPR knockout (KO) mice and found that although these mice had normal lymphocyte numbers, γ c/TSLPR double KO mice had a greater lymphoid defect than γ c KO mice. This indicates that TSLP contributes to lymphoid development and accounts for some of the residual lymphoid development in γ c KO mice and presumably in patients with X-linked severe combined immunodeficiency. Injection of TSLP into γ c KO mice induced the expansion of T and B cells. Moreover, sublethally irradiated TSLPR KO mice showed weaker recovery of lymphocyte populations than wild-type (WT) littermates, even when neutralizing anti–IL-7 antibodies were injected. Interestingly, TSLP preferentially stimulated the proliferation and survival of CD4 + single positive thymocytes and peripheral T cells in vitro. Additionally, CD4 + T cells from TSLPR KO mice expanded less efficiently than WT CD4 + T cells in irradiated hosts, and TSLP preferentially expanded CD4 + T cells both in vitro and in vivo. Thus, as compared with other known cytokines, TSLP is distinctive in exhibiting a lineage preference for the expansion and survival of CD4 + T cells.

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          Most cited references30

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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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              Cytokine control of memory T-cell development and survival.

              Evidence has accumulated that cytokines have a fundamental role in the differentiation of memory T cells. Here, we follow the CD8+ T cell from initial activation to memory-cell generation, indicating the checkpoints at which cytokines determine the fate of the T cell. Members of the common cytokine-receptor gamma-chain (gammac)-cytokine family--in particular, interleukin-7 (IL-7) and IL-15--act at each stage of the immune response to promote proliferation and survival. In this manner, a stable and protective, long-lived memory CD8+ T-cell pool can be propagated and maintained.
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                Author and article information

                Journal
                J Exp Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                19 July 2004
                : 200
                : 2
                : 159-168
                Affiliations
                [1 ]Laboratory of Molecular Immunology, [2 ]Pediatric Oncology Branch, National Cancer Institute, and [3 ]The National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
                [4 ]McKusick-Nathans Institute of Genetic Medicine, John Hopkins University, Baltimore, MD 21287
                Author notes

                Address correspondence to Warren J. Leonard, Laboratory of Molecular Immunology, Building 10, Room 7N252, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-0098; Fax: (301) 402-0971; e-mail: wjl@ 123456helix.nih.gov

                Article
                20031975
                10.1084/jem.20031975
                2212020
                15263024
                dd82613c-e957-4109-be40-7733186b92c7
                Copyright © 2004, The Rockefeller University Press
                Categories
                Article

                Medicine
                il-7,knockout mice,cd8 t cells,thymocyte development,scid
                Medicine
                il-7, knockout mice, cd8 t cells, thymocyte development, scid

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