Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 1906-1914
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, and
James N. Ihle
From the Howard Hughes Medical Institute and the Departments of
Biochemistry, Hematology-Oncology, Immunology, and Genetics, St. Jude
Children's Research Hospital, Memphis, TN; and the Departments of
Pediatrics, Pathology, and Biochemistry, University of Tennessee
Medical School, Memphis, TN.
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.
