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https://hdl.handle.net/2440/8677
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Type: | Journal article |
Title: | Reconstitution of Early Lymphoid Proliferation and Immune Function in Jak3-Deficient Mice by Interleukin-3 |
Author: | Brown, M. Nosaka, T. Tripp, R. Brooks, J. van Deursen, J. Brenner, M. Doherty, P. Ihle, J. |
Citation: | Blood, 1999; 94(6):1906-1914 |
Publisher: | AMER SOC HEMATOLOGY |
Issue Date: | 1999 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Michael P. Brown, Tetsuya Nosaka, Ralph A. Tripp, James Brooks, Jan M.A. van Deursen, Malcolm K. Brenner, Peter C. Doherty and James N. Ihle |
Abstract: | Expansion of early lymphoid progenitors requires interleukin-7 (IL-7), which functions through c-mediated receptor activation of Jak3. Jak3 deficiency is a cause of severe combined immunodeficiency (SCID) in humans and mice. IL-3 activates many of the same signaling pathways as IL-7, such as Stat5, but achieves this effect through the activation of Jak2 rather than Jak3. We hypothesized that expansion of an IL-7-responsive precursor population through a Jak3-independent pathway using IL-3 may stimulate early lymphoid progenitors and restore lymphopoiesis in Jak3/ mice. Newborn Jak3/ mice that were injected with IL-3 demonstrated thymic enlargement, a 2- to 20-fold increase in thymocyte numbers, and up to a 10-fold expansion in the number of CD4+, CD8+, and B220+/IgM+ splenic lymphocytes, consistent with an effect upon an early lymphoid progenitor population. In contrast to control mice, IL-3-treated Jak3/ mice challenged with the allogeneic major histocompatibility complex (MHC) class I-bearing tumor P815 developed a specific CD8-dependent cytotoxic T lymphocyte (CTL) response. IL-3-treated mice also mounted influenza-specific CTL responses and survival was prolonged. The beneficial effects of IL-3 are proposed to be produced by stimulation of a lymphoid precursor population of IL-7R+/IL-3R+ cells that we identified in wild-type bone marrow. In vitro, we show that an early IL-7R+ lymphoid progenitor population expresses IL-3R and proliferates in response to IL-3 and that IL-3 activates Stat5 comparably to IL-7. Clinically, IL-3 may therefore be useful treatment for X-linked and Jak3-deficient SCID patients who lack bone marrow donors. |
Keywords: | Lymphocytes Bone Marrow Cells Hematopoietic Stem Cells Animals Mice, Inbred BALB C Mice, Knockout Mice Mice, SCID Interleukin-3 Receptors, Interleukin-7 Interleukin-7 Flow Cytometry Lymphocyte Activation Signal Transduction Protein-Tyrosine Kinases Janus Kinase 3 |
Description: | Copyright © 1999 by American Society of Hematology |
DOI: | 10.1182/blood.v94.6.1906.418k32_1906_1914 |
Published version: | http://bloodjournal.hematologylibrary.org/cgi/content/abstract/94/6/1906?maxtoshow=&HITS=&hits=&RESULTFORMAT=&author1=Brown&title=Reconstitution+of+Early+Lymphoid+Proliferation+and+Immune+Function+in+Jak3-Deficient+Mice+by+Interleukin-3&andorexacttitle=phrase&searchid=1&FIRSTINDEX=0&volume=94&firstpage=1906&resourcetype=HWCIT |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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