Targeting Janus tyrosine kinase 3 (JAK3) with an inhibitor induces secretion of TGF-β by CD4+ T cells

摘要

Regulatory T cells (Tregs) are critical for the peripheral maintenance of the autoreactive T cells in autoimmune disorders such as type 1 diabetes (T1D).Pharmacological inhibition of Janus tyros.he kinase 3 (JAK3) has been proposed as a basis for new treatment modalities against autoimmunity and allogeneic responses.Targeting JAK3 with an inhibitor has previously been shown to exhibit protective action against the development of T1D in non-obese diabetic (NOD) mice.As the mechanism of such preventative action has been unknown,we hypothesized that JAK3 inhibition induces generation of Tregs.Here,we show that the JAK3 inhibitor 4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131) suppresses proliferation of short-term cultured NOD CD4+ T cells through induction of apoptosis,while promoting survival of a particular population of long-term cultured cells.It was found that the surviving cells were not of the CD4+CD25+FoxP3+ phenotype.They secreted decreased amounts of IL-10,IL-4 and interferon (IFN)-γ compared to the cells not exposed to the optimal concentrations of JAK3 inhibitor.However,an elevated transforming growth factor (TGF)-β secretion was detected in their supernatants.In vivo treatment of prediabetic NOD mice with WHI-P131 did not affect the frequency and number of splenic and pancreatic lymph node CD4+FoxP3+ Tregs,while generating an elevated numbers of CD4+FoxP3-TGF-β-secreting T cells.In conclusion,our data suggest an induction of TGF-β-secreting CD4+ T cells as the underlying mechanism for antidiabetogenic effects obtained by the treatment with a JAK3 inhibitor.To our knowledge,this is the first report of the JAK3 inhibitor activity in the context of the murine Tregs.