Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1
NATURE COMMUNICATIONS
Authors: Bothur, Evita; Raifer, Hartmann; Haftmann, Claudia; Stittrich, Anna-Barbara; Bruestle, Anne; Brenner, Dirk; Bollig, Nadine; Bieringer, Maria; Kang, Chol-Ho; Reinhard, Katharina; Camara, Baerbel; Huber, Magdalena; Visekruna, Alexander; Steinhoff, Ulrich; Repenning, Antje; Bauer, Uta-Maria; Sexl, Veronika; Radbruch, Andreas; Sparwasser, Tim; Mashreghi, Mir-Farzin; Mak, Tak Wah; Lohoff, Michael
Abstract
Regulatory T-cells induced via IL-2 and TGF beta in vitro (iTreg) suppress immune cells and are potential therapeutics during autoimmunity. However, several reports described their re-differentiation into pathogenic cells in vivo and loss of their key functional transcription factor (TF) FOXP3 after T-cell antigen receptor (TCR)-signalling in vitro. Here, we show that TCR-activation antagonizes two necessary TFs for foxp3 gene transcription, which are themselves regulated by phosphorylation. Although the tyrosine phosphatase PTPN2 is induced to restrain IL-2-mediated phosphorylation of the TF STAT5, expression of the TF FOXO1 is downregulated and miR-182, a suppressor of FOXO1 expression, is upregulated. TGFb counteracts the FOXP3-depleting TCR-signal by reassuring FOXO1 expression and by re-licensing STAT5 phosphorylation. Overexpressed phosphorylation-independent active versions of FOXO1 and STAT5 or knockdown of PTPN2 restores FOXP3 expression despite TCR-signal and absence of TGF beta. This study suggests novel targets for stabilisation and less dangerous application of iTreg during devastating inflammation.
Non-specific immune responses and intestinal immunity of common carp (Cyprinus carpio) fed Jujube (Ziziphus jujube) fruit extract
AQUACULTURE RESEARCH
Authors: Hoseinifar, Seyed Hossein; Zou, Hassan Khodadadian; Paknejad, Hamed; Ahmadifar, Ehsan; Hien Van Doan
Abstract
This study investigated the effects of Jujube (Ziziphus jujube) fruit extract (JFE) as an excellent source of nutrients and phytochemicals on the innate immune responses and expression of genes involved in intestinal immunity of common carp (Cyprinus carpio) fingerlings. Three hundred healthy carps (10.78 +/- 0.05g) fingerlings were randomly allocated to 12 fibre glass tanks (300L; 15 fish per tank) and fed for 8weeks with experimental diets which contained different levels of JFE (0%, 0.25%, 0.5%, or 1%). Thereafter, serum non-specific immune parameters [total immunoglobulin (Ig) as well as alternative complement (ACH50) and lysozyme activity (SL)] and expression of genes involved in intestinal immunity (lyz, tnf-alpha, il1b, il8, il10, and tgfb) were measured. The results revealed a significant elevation of Ig level in the JFE-fed fish (p<0.05) over the control fish. However, there was no significant difference among treated groups in case of serum total Ig. The highest levels of SL and ACH50 were observed in fish fed 1% of JFE. Nonetheless, no significant difference was noticed regarding SL and ACH50 of control and other supplemented groups (0.25% and 0.5% JFE). Also, expression of lyz, tnf-alpha, and il1b genes increased significantly (p<0.05) in JFE-fed fish, in a dose-dependent manner. On the other hand, significant (p<0.05) down-regulation of il110 and tgfb were noticed in treated groups. The present findings suggested that extraction of Jujube, Z. jujube fruit, possesses beneficial effects on immune responses of common carp.