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|Title:||Reconstitution of Early Lymphoid Proliferation and Immune Function in Jak3-Deficient Mice by Interleukin-3|
van Deursen, J.
|Citation:||Blood, 1999; 94(6):1906-1914|
|Publisher:||AMER SOC HEMATOLOGY|
|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|
|Appears in Collections:||Medicine publications|
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