Targeting Janus tyrosine kinase 3 (JAK3) with an inhibitor induces secretion of TGF-β by CD4+ T cells.
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 tyrosine 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.
Department of Biological Sciences, St. Cloud State University, St. Cloud, MN 56301, USA. mcetkoviccvrlje@stcloudstate.edu
Marina
M
Cetkovic-Cvrlje
Marin
M
Olson
Ketaki
K
Ghate
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018791:CD4 Lymphocyte Count; D002478:Cells, Cultured; D019610:Cytoprotection; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D051379:Mice; D016688:Mice, Inbred NOD; D011799:Quinazolines / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D011799:Quinazolines; D016212:Transforming Growth Factor beta; C116180:WHI P131; D053616:Janus Kinase 3