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

作     者：Marina Cetkovic-Cvrlje Marin Olson Ketaki Ghate 

作者机构：Department of Biological Sciences St. Cloud State University St. Cloud MN USA Laboratory for Immunology St. Cloud State University St. Cloud MN USA 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2012年第9卷第4期

页      面：350-360页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 071009[理学-细胞生物学] 09[农学] 0901[农学-作物学] 090102[农学-作物遗传育种] 

基　　金：SCSU OSP Student Research Grants to MO and KG SCSU OSP Faculty Grants to MCC SCSU Hellervik Prize 国家自然科学基金 

主　　题：FoxP3 Janus tyrosine kinase 3 (JAK3) inhibition regulatory T cells (Tregs) TGF-β type 1 diabetes (TID) 

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 （TID）. 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 T 1D 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-IO, IL-4 and interferon （IFN）-y 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.