Supraphysiological Levels of IL-2 in Jak3-Deficient Mice Promote Strong Proliferative Responses of Adoptively Transferred Naive CD8+ T Cells

Abstract

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 (γc) 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 γc 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.

Immunomodulatory effect of long‐term oclacitinib maleate therapy in dogs with atopic dermatitis

“…Likewise, oclacitinib did not demonstrate any in vitro proliferative effect in treated canine T cells 12 . Furthermore, another in vitro evaluation has reported that oclacitinib inhibits JAK1‐dependent cytokines, an important mechanism to induce IL‐2 production 12 and a critical cytokine that triggers the lymphoproliferative effect 27 …”

“…12 Furthermore, another in vitro evaluation has reported that oclacitinib inhibits JAK1dependent cytokines, an important mechanism to induce IL-2 production 12 and a critical cytokine that triggers the lymphoproliferative effect. 27 The cytokine profile is considered to be an important biomarker to determine the pro-inflammatory and/or immunosuppressive effect on the canine immune system, 28 and could contribute to the analysis of the immune response pattern in cAD. 11,29 In blood circulation, free cytokine concentrations typically are low and the reported values vary considerably.…”