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.