Reconstitution of early lymphoid proliferation and immune function in Jak3-deficient mice by interleukin-3

Michael P. Brown, Tetsuya Nosaka, Ralph A. Tripp, James Brooks, Jan M.A. Van Deursen, Malcolm K. Brenner, Peter C. Doherty, James N. Ihle

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Expansion of early lymphoid progenitors requires interleukin-7 (IL-7), which functions through γ(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-7Rα+/IL-3Rα+ 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.

Original languageEnglish (US)
Pages (from-to)1906-1914
Number of pages9
JournalBlood
Volume94
Issue number6
DOIs
StatePublished - Sep 15 1999

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Brown, M. P., Nosaka, T., Tripp, R. A., Brooks, J., Van Deursen, J. M. A., Brenner, M. K., Doherty, P. C., & Ihle, J. N. (1999). Reconstitution of early lymphoid proliferation and immune function in Jak3-deficient mice by interleukin-3. Blood, 94(6), 1906-1914. https://doi.org/10.1182/blood.v94.6.1906.418k32_1906_1914