Supraphysiological Levels Of Il-2 In Jak3-Deficient Mice Promote Strong Proliferative Responses Of Adoptively Transferred Naive Cd8(+) T Cells

The antigen-independent, strong proliferative responses of naive CD8(+) T cells have been well demonstrated in a particular strain of mice lacking IL-2 receptors. This type of proliferation is mainly driven by common gamma-chain (gamma(c)) cytokines, such as IL-2, IL-7, and IL-15, present at abnormally high levels in these mice. Similarly, in the present study, we showed that mice lacking Janus kinase 3 (Jak3), a tyrosine kinase crucial for gamma(c) cytokine signaling, could induce strong proliferation of adoptively transferred naive CD8(+) T cells. This proliferation was also independent of antigenic stimulation, but heavily dependent on IL-2, as evidenced by the failure of proliferation of adoptively transferred IL-2 receptor alpha- and beta-chain-deficient naive CD8(+) T cells. Consistent with this, Jak3 (-/-) mice showed elevated serum levels of IL-2 compared to wild-type mice, and interestingly, IL-2 production was due to high levels of accumulation of activated CD4(+) T cells in Jak3 (-/-) mice along with defective CD4(+) T regulatory cells. Collectively, these findings reveal previously unidentified unique immune contexts of Jak3 (-/-) mice that cause robust IL-2-driven T cell expansion and have a clinical implication for designing a treatment strategy for human patients with loss-of-function genetic mutations of Jak3.