Janus kinase 3 (Jak3) is essential for common cytokine receptor gamma chain (gamma(c))-dependent signaling: comparative analysis of gamma(c), Jak3, and gamma(c) and Jak3 double-deficient mice.
The common cytokine receptor gamma chain (gamma(c)) is an essential receptor component for IL-2, IL-4, IL-7, IL-9 and IL-15, and thereby gamma(c)-deficient mice exhibit impaired T cell and B cell development. The Janus family tyrosine kinase 3 (Jak3) is known to be associated with gamma(c), and the reported phenotypes of gamma(c)-deficient (gamma(c)(-)) and Jak3-deficient (Jak3(-)) mice are similar, indicating that Jak3 is an essential transducer of gamma(c)-dependent signals. Nevertheless, certain differences have been suggested related to the range of actions of gamma(c) and Jak3. To clarify whether gamma(c)-dependent cytokines can partially transduce their signals without Jak3, we compared lymphocyte development in gamma(c)(-), Jak3(-), and gamma(c) and Jak3 double-deficient (gamma(c)(-)Jak3(-)) mice in the same genetic background. With the exception that T and B cells in Jak3(-) mice express high levels of gamma(c), the defects in thymocyte and peripheral T cell and B cell development are indistinguishable among gamma(c)(-), Jak3(-) and gamma(c)(-)Jak3(-) mice. Interestingly, although Bcl-2 induction was previously suggested to be Jak3-independent, IL-7 cannot induce Bcl-2 expression in CD4 single-positive (SP) thymocytes in either gamma(c)(-) or Jak3(-) mice nor can IL-7 rescue CD4 SP thymocytes from dexamethasone-induced cell death in gamma(c)(-) or Jak3(-) mice. These results indicate that Jak3 is absolutely essential for gamma(c)-dependent T cell and B cell development, and for gamma(c)-dependent prevention of thymocyte apoptosis.
Suzuki
K
K
Department of Internal Medicine II, Chiba University School of Medicine, Chiba 260-8670, Japan.
Nakajima
H
H
Saito
Y
Y
Saito
T
T
Leonard
W J
WJ
Iwamoto
I
I
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002454:Cell Differentiation; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D019254:Genes, bcl-2; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053616:Janus Kinase 3; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics*; D018121:Receptors, Cytokine / Q000172:deficiency / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D019076:Transgenes
D016692:Receptors, Antigen, T-Cell, gamma-delta; D018121:Receptors, Cytokine; D015375:Receptors, Interleukin-2; D018799:Intercellular Adhesion Molecule-1; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3