T cell development and activation in Jak3-deficient mice

Jak3, a member of the Janus family of tyrosine kinases, participates in signaling through cytokine receptors that contain the common γ‐chain, including the receptors for interleukin (IL)‐2, IL‐4, IL‐7, IL‐9, and IL‐15. Jak3‐ and γc‐deficient mice have pleiotropic defects that can be attributed to their inability to respond to multiple specific cytokines. A great deal of recent work has focused on the T cell defects in these mutant mice. Specifically, Jak3‐ and γc‐deficient mice have small thymuses revealing a defect in T cell development, and in addition, have functionally unresponsive peripheral T cells with an activated/memory cell phenotype. The thymic defect in these mutant mice strongly resembles that seen in IL‐7 and IL‐7 receptor knockout mice, suggesting that the lack of IL‐7 receptor signaling accounts for this defect in Jak3‐/‐ and γc– mice. To characterize this defect further, we have examined the earliest stages of T cell development in adult and fetal Jak3‐/‐ thymuses. These studies identify two discrete developmental defects at the CD4–CD8– stage of T cell maturation. Analyses of peripheral T cells in Jak3‐/‐and γc– mice have also revealed a number of abnormalities. All of the T cells in these mutant mice have an activated phenotype and a large fraction of them are proliferating in vivo. In addition, Jak3‐/‐ and γc– T cells are more prone to undergo apoptosis than wild‐type T cells. Together, these features account for the decreased IL‐2 secretion by in vitro‐stimulated Jak3‐/‐ T cells. Overall, many of the lymphoid defects of Jak3‐ and γc‐deficient mice can be accounted for by the lack of IL‐7R and IL‐2R signaling; however, other cytokine systems must also be involved in maintaining peripheral T cell homeostasis. J. Leukoc. Biol. 63: 669–677; 1998.