Dysregulated myelopoiesis in mice lacking Jak3.
Jak3 is a cytoplasmic tyrosine kinase that associates with the common chain of the interleukin-2 (IL-2) receptor and is involved in the function of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Mice deficient in Jak3 have few T and B cells, and no natural killer cells. Herein we show that the myeloid lineages in these mice are also affected by the loss of Jak3. Mice lacking Jak3 exhibit splenomegaly by 4 months of age. Peripheral blood smears show an increase in the number of neutrophils and cells of the monocytic lineage. Flow cytometry of splenocytes and peripheral blood show a significant increase in FcgammaRII/III(FcgammaR)/Mac-1, FcgammaR/Gr-1, and FcgammaR/F4/80 double-positive cells in -/- and +/- mice compared to wild-type mice, consistent with an expansion of cells of the myeloid lineages. In addition, as the mice age, F4/80 and CD3 positive mononuclear cells infiltrate the kidneys, lungs, and liver of these mice. When Jak3-/- mice are crossed with a transgenic mouse expressing Jak3 in the T and NK cell compartments, the splenomegaly and myeloid expansion are accentuated. These data correlate with the constitutive activation of T cells in the periphery as the transgenic cells lose their expression of Jak3 with age. However, when Jak3-/- mice are crossed with RAG-1-deficient animals, no splenomegaly or myeloid expansion is apparent. These results indicate that the loss of Jak3 in the T-cell compartment drives the expansion of the myeloid lineages.
Divisions of Molecular Microbiology and Cardiology, Departments of Pathology and Medicine, Washington University School of Medicine, St Louis, MO, USA.
W J
WJ
Grossman
J W
JW
Verbsky
L
L
Yang
L J
LJ
Berg
L E
LE
Fields
D D
DD
Chaplin
L
L
Ratner
D000818:Animals; D005434:Flow Cytometry; D017353:Gene Deletion; D018398:Homeodomain Proteins / Q000502:physiology; D007150:Immunohistochemistry; D053616:Janus Kinase 3; D019891:Leukopoiesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000502:physiology
D018398:Homeodomain Proteins; D017452:Receptors, IgG; D015375:Receptors, Interleukin-2; C064658:RAG-1 protein; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3