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      Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets

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          Abstract

          Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-human clinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4 + and CD8 + T cells. This T cell expansion caused a significant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8 + effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profile, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodeficiency virus), or iatrogenic (chemotherapy) lymphocyte depletion.

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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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              Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency.

              Severe combined immunodeficiency (SCID) is caused by multiple genetic defects. The most common form of SCID, X-linked SCID (XSCID), results from mutations in IL2RG (ref. 4), which encodes the common cytokine receptor gamma chain (gamma(c)) that is shared by the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors. In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to gamma(c) and is required for gamma(c)-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal (T(-)B(+)NK(-)SCID). Some SCID patients lack T cells but retain NK cells. Given diminished T-cell development in Il7- or Il7r-deficient mice and that Il/7r-deficient mice have NK cells, we hypothesized that T(-)B(+)NK(+) SCID might result from defective IL-7 signalling, although apparent differences in the role of the IL-7/IL-7R pathway in humans and mice in T-cell and B-cell development have been suggested. We now demonstrate that defective IL7R expression causes T(-)B(+)NK(+) SCID, indicating that the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Ralpha signalling.
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                Author and article information

                Journal
                J Exp Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                7 July 2008
                : 205
                : 7
                : 1701-1714
                Affiliations
                [1 ]Experimental Transplantation and Immunology Branch; [2 ]Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute; [3 ]Departments of Radiology; [4 ]Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892
                [5 ]Cytheris Inc., Rockville, MD 20850
                [6 ]Methodist Hospital, Texas Medical Center, Houston, TX 77021
                [7 ]Biostatistics and Data Management Section, National Cancer Institute, [8 ]The Cancer Center at Hackensack University Medical Center, Hackensack, NJ 07601
                Author notes

                CORRESPONDENCE Claude Sportès: csportes@ 123456mail.nih.gov

                Article
                20071681
                10.1084/jem.20071681
                2442646
                18573906
                9308a60d-96a2-4702-b42a-e067b836c194
                © 2008 Sportès et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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