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      Interleukin (IL)-15 and IL-7 Jointly Regulate Homeostatic Proliferation of Memory Phenotype CD8 + Cells but Are Not Required for Memory Phenotype CD4 + Cells

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          Abstract

          The overall size and composition of the pool of naive and memory T cells are tightly regulated by homeostatic mechanisms. Recent work has shown that homeostasis of naive T cells is controlled by two factors, self-major histocompatibility complex (MHC)/peptide ligands and a cytokine, interleukin (IL)-7. In particular, contact with these two factors is required for naive CD4 + and CD8 + cells to undergo “homeostatic” proliferation, i.e., proliferation induced as a consequence of severe T cell depletion. In contrast to naive T cells, the factors that drive memory T cells to undergo homeostatic proliferation are poorly understood. To address this issue, purified memory phenotype CD4 + and CD8 + cells from normal mice were adoptively transferred into various gene-knockout mice rendered T cell–deficient by sublethal irradiation. Three findings are reported. First, unlike naive T cells, homeostatic proliferation of memory T cells is largely MHC independent. Second, memory CD8 + cells can utilize either IL-7 or IL-15 to undergo homeostatic proliferation; however, in the absence of both IL-7 and IL-15, homeostatic proliferation fails to occur. Third, unlike memory CD8 + cells, homeostatic proliferation of memory CD4 + cells is independent of IL-7 and IL-15 (also IL-4). Thus, the homeostatic proliferation mechanisms that control memory CD8 + cells and memory CD4 + cells are quite distinct.

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          Most cited references38

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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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            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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              IL-7 is critical for homeostatic proliferation and survival of naive T cells.

              In T cell-deficient conditions, naive T cells undergo spontaneous "homeostatic" proliferation in response to contact with self-MHC/peptide ligands. With the aid of an in vitro system, we show here that homeostatic proliferation is also cytokine-dependent. The cytokines IL-4, IL-7, and IL-15 enhanced homeostatic proliferation of naive T cells in vitro. Of these cytokines, only IL-7 was found to be critical; thus, naive T cells underwent homeostatic proliferation in IL-4(-) and IL-15(-) hosts but proliferated minimally in IL-7(-) hosts. In addition to homeostatic proliferation, the prolonged survival of naive T cells requires IL-7. Thus, naïve T cells disappeared gradually over a 1-month period upon adoptive transfer into IL-7(-) hosts. These findings indicate that naive T cells depend on IL-7 for survival and homeostatic proliferation.
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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
                17 June 2002
                : 195
                : 12
                : 1523-1532
                Affiliations
                Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
                Author notes

                Address correspondence to Charles D. Surh, Dept. of Immunology, IMM26, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: 858-784-2006; Fax: 858-784-8227; E-mail: csurh@ 123456scripps.edu

                Article
                020066
                10.1084/jem.20020066
                2193564
                12070280
                02fe6ac3-bde5-451d-b307-9d944425460e
                Copyright © 2002, The Rockefeller University Press
                Categories
                Article

                Medicine
                lymphopenia,t lymphocytes,homeostasis,cytokines,memory
                Medicine
                lymphopenia, t lymphocytes, homeostasis, cytokines, memory

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