Promoted Treg Cell Differentiation Research Articles

The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells.

An imbalance in the lineages of immunosuppressive regulatory T cells (Treg cells) and the inflammatory TH17 subset of helper T cells leads to the development of autoimmune and/or inflammatory disease. Here we found that TAZ, a coactivator of TEAD transcription factors of Hippo signaling, was expressed under TH17 cell-inducing conditions and was required for TH17 differentiation and TH17 cell-mediated inflammatory diseases. TAZ was a critical co-activator of the TH17-defining transcription factor RORγt. In addition, TAZ attenuated Treg cell development by decreasing acetylation of the Treg cell master regulator Foxp3 mediated by the histone acetyltransferase Tip60, which targeted Foxp3 for proteasomal degradation. In contrast, under Treg cell-skewing conditions, TEAD1 expression and sequestration of TAZ from the transcription factors RORγt and Foxp3 promoted Treg cell differentiation. Furthermore, deficiency in TAZ or overexpression of TEAD1 induced Treg cell differentiation, whereas expression of a transgene encoding TAZ or activation of TAZ directed TH17 cell differentiation. Our results demonstrate a pivotal role for TAZ in regulating the differentiation of Treg cells and TH17 cells.

The Nrf2 activator dimethyl fumarate inhibits acute graft-versus-host disease with retention of graft-versus-tumor effects

Abstract Dimethyl fumarate (DMF), an activator of Nrf2, has been shown to have anti-inflammatory and immunomodulatory properties without significant immunosuppression. we therefore hypothesized that DMF could be a new candidate drug for the treatment of aGVHD with retention of GVT effect. Lethally irradiated BALB/c mice transplanted with B6 bone marrow plus splenocytes were administered DMF or vehicle solution by gavage daily from day -3 to day 3. DMF treatment inhibited aGVHD, accompanied by less weight loss and lower clinical score. DMF is capable of significantly inhibiting proliferation of alloreactive T cells in a dose-dependent manner in mixed lymphocyte reaction assay. Furthermore, the percentages of CD69+T cells and IFN-γ expressing T cells, were significantly increased in aGVHD target organs from DMF recipients. In addition, DMF treatment markedly increased the frequencies of Treg cells in target organs. Depletion of CD25+ cells in DMF recipients aggravated aGVHD mortality compared with IgG control recipients. Moreover, Treg polarizing assay suggested that DMF could promote Treg cell differentiation in vitro in a dose-dependent manner. In addition, No protective effects of DMF were observed in mice transplanted with BM and challenged with leukemia cells. However, DMF treatment significantly prolonged the survival in tumor-bearing mice that received an allogeneic BMT with donor splenocytes. we also observed that donor T cells recovered from DMF-treated recipients and controls showed comparable cytolytic activity against leukemia cells. In conclusion, our findings demonstrated that activation of Nrf2 with DMF may be of significant use in preventing aGVHD and preserving GVT responses.

Probiotic Metabolites Promote Anti‐inflammatory Functions of Immune Cells

The microbiome is an important factor in human health and disease. Recent reports demonstrate that short‐chain fatty acids (SCFA), type of bacterial metabolites, ameliorate autoimmune diseases, indicating a link between the gut microbiome, immune cells and inflammation. In this study, we investigated the potential health benefits of probiotic bacterial metabolites by evaluating their functions in regulating the differentiation of anti‐inflammatory and pro‐inflammatory immune cells, and determining the underlying mechanisms.Using conditioned media from the probiotic bacteria, Lactococcus lactis and Lactobacillus reuteri, we demonstrated that bacterial metabolites induced differentiation of immunosuppressive anti‐inflammatory T‐regulatory (Treg) cells. Consistently, butyrate, a bacterial‐derived SCFA, enhanced the differentiation of Treg cells from naïve CD4+ T cells. Furthermore, butyrate inhibited the maturation of pro‐inflammatory antigen‐presenting dendritic cells (DCs) from hematopoietic progenitor cells. Mechanistically, we found that butyrate promoted Treg cell differentiation via increasing expression of transcription factor Foxp3 and the anti‐inflammatory cytokine IL‐10. In addition, it suppressed the maturation of DCs by inhibiting the expression of CD11c and MHC Class II, critical molecules for pathogenic CD4+ T cell activation. Taken together, these studies reveal novel functions of probiotic metabolites, SCFA, in regulating the differentiation/activation of anti‐inflammatory and pro‐inflammatory immune cells, thus inhibiting inflammation and promoting human health.Support or Funding InformationThis work was supported by the National Institute of Health grants NS057563 (E.N.B.)

Decidual vascular endothelial cells promote maternal–fetal immune tolerance by inducing regulatory T cells through canonical Notch1 signaling

Adaptation of the maternal immune response to accommodate the semiallogeneic fetus is necessary for pregnancy success. However, the mechanisms by which the fetus avoids rejection despite expression of paternal alloantigens remain incompletely understood. Regulatory T cells (Treg cells) are pivotal for maintaining immune homeostasis, preventing autoimmune disease and fetus rejection. In this study, we found that maternal decidual vascular endothelial cells (DVECs) sustained Foxp3 expression in resting Treg cells in vitro. Moreover, under in vitro Treg cell induction condition with agonistic antibodies and transforming growth factor (TGF)-β, DVECs promoted Treg cell differentiation from non-Treg conventional T cells. Consistent with the promotion of Treg cell maintenance and differentiation, Treg cell-associated gene expression such as TGF-β, Epstein-Barr-induced gene-3, CD39 and glucocorticoid-induced tumor necrosis factor receptor was also increased in the presence of DVECs. Further study revealed that DVECs expressed Notch ligands such as Jagged-1, Delta-like protein 1 (DLL-1) and DLL-4, while Treg cells expressed Notch1 on their surface. The effects of DVECs on Treg cells was inhibited by siRNA-induced knockdown of expression of Jagged-1 and DLL-1 in DVECs. Downregulation of Notch1 in Treg cells using lentiviral shRNA transduction decreased Foxp3 expression in Treg cells. Adoptive transfer of Notch1-deficient Treg cells increased abortion rate in a murine semiallogeneic pregnancy model. Taken together, our study suggests that maternal DVECs are able to maintain decidual Treg cell identity and promote Treg cell differentiation through activation of Notch1 signal pathway in Treg cells and subsequently inhibit the immune response against semiallogeneic fetuses and preventing spontaneous abortion.

Histamine enhances HIV-1-induced modulation of dendritic cells to skew naïve T cell differentiation toward regulatory T cells

Altered cytokine profiles and imbalanced frequencies of CD4+ T helper cell subsets are thought to be linked with HIV-1/AIDS pathogenesis, but the causes need to be further clarified. Histamine, a biogenic amine with many functions, shows enhancement in HIV-1 infected individuals, which are considered to link with disease progression, but is poorly understood. This study investigated histamine-assisted HIV-1 modulation of dendritic cell (DC) functions. Histamine and HIV-1 showed a synergistic role in induction of interleukin-10; histamine inhibited HIV-1-induced IL-12 production from MDDCs (monocyte-derived DCs); notably, histamine augmented HIV-1-induced MDDC functional polarization and skewed naïve T cell differentiation toward regulatory T cells (Tregs). The results indicate the novel role of histamine in HIV-1-induced DC functional regulation, which promoted Treg cell differentiation and up-regulated immunosuppressive factors. These findings help to bridge the correlation between elevated histamine and increased Treg cell frequency in HIV-1 infected individuals, and add to our understanding of HIV-1-induced immunosuppression.

Baicalin, a natural compound, promotes regulatory T cell differentiation.

BackgroundCD4+CD25+Foxp3+ regulatory T (Treg) cells inhibit autoimmunity and protect against tissue injury. The development of these Treg cells is controlled by the regulator protein Foxp3, which can be enhanced by the in vitro activation of Foxp3 in the presence of transforming growth factor-beta. However, little is known about alternative methods, such as the use of natural products, for controlling Foxp3-mediated Treg cell differentiation.MethodHEK 293 T cells were transfected with Foxp3 expression plasmid, and then treated with different compounds, Foxp3 mRNA expression was determined by real-time RT-PCR. CD4+CD25-T cells were stimulated with Baicalin, Foxp3 protein expression were analyzed by flow cytometry and confocal microscopy, the regulatory function of T cells stimulated with Baicalin was detected by the carboxyfluorescien succinimidyl ester.ResultsWe demonstrated that Baicalin, a compound isolated from the Chinese herb Huangqin, induced Foxp3 protein expression in cultured T cells, promoted Treg cell differentiation and regulatory activity. Our data also indicated that Baicalin restored Foxp3 expression following its initial interleukin-6-mediated inhibition and induced Foxp3 expression in vitro.ConclusionsThese data suggest that Baicalin may promote Treg cell differentiation and regulatory activity and may serve as a promising natural immunosuppressive compound for treating autoimmune inflammatory diseases.