ABSTRACT
T helper type 9 (Th9) cells play important roles in immune responses by producing interleukin-9 (IL-9). Several transcription factors are responsible for Th9 cell differentiation; however, transcriptional regulation of Th9 cells is not fully understood. Here, it is shown that Id1 is an essential transcriptional regulator of Th9 cell differentiation. Id1 is induced by IL-4 and TGF-ß. Id1-deficient naïve CD4 T cells fail to differentiate into Th9 cells, and overexpression of Id1 induce expression of IL-9. Mass spectrometry analysis reveals that Id1 interacts with Tcf3 and Tcf4 in Th9 cells. In addition, RNA-sequencing, chromatin immunoprecipitation, and transient reporter assay reveal that Tcf3 and Tcf4 bind to the promoter region of the Il9 gene to suppress its expression, and that Id1 inhibits their function, leading to Th9 differentiation. Finally, Id1-deficient Th9 cells ameliorate airway inflammation in an animal model of asthma. Thus, Id1 is a transcription factor that plays an essential role in Th9 cell differentiation by inhibiting Tcf3 and Tcf4.
Subject(s)
Interleukin-9 , Transcription Factors , Animals , Transcription Factors/genetics , Interleukin-9/genetics , Interleukin-9/metabolism , T-Lymphocytes, Helper-Inducer/metabolism , Gene Expression Regulation , Cell Differentiation/physiologyABSTRACT
Regulatory T (Treg) cells play an important role in immune homeostasis by inhibiting cells within the innate and adaptive immune systems; therefore, the stability and immunosuppressive function of Treg cells need to be maintained. In this study, we found that the expression of insulin receptor substrate 1 (IRS1) by Treg cells was lower than that by conventional CD4 T cells. IRS1-overexpressing Treg cells showed the downregulated expression of FOXP3, as well as Treg signature markers CD25 and CTLA4. IRS1-overexpressing Treg cells also showed diminished immunosuppressive functions in an in vitro suppression assay. Moreover, IRS1-overexpressing Treg cells were unable to suppress the pathogenic effects of conventional T cells in a transfer-induced colitis model. IRS1 activated the mTORC1 signaling pathway, a negative regulator of Treg cells. Moreover, IRS1 destabilized Treg cells by upregulating the expression of IFN-γ and Glut1. Thus, IRS1 acts as a negative regulator of Treg cells by downregulating the expression of FOXP3 and disrupting stability.
Subject(s)
CD4-Positive T-Lymphocytes , T-Lymphocytes, Regulatory , Forkhead Transcription Factors/metabolism , Immunosuppressive Agents/pharmacology , Insulin Receptor Substrate Proteins/genetics , Insulin Receptor Substrate Proteins/metabolism , Interleukin-2 Receptor alpha Subunit/metabolism , Signal Transduction , Mechanistic Target of Rapamycin Complex 1/metabolismABSTRACT
Regulatory T (Treg) cells play an essential role in maintaining immune homeostasis, but the suppressive function of Treg cells can be an obstacle in the treatment of cancer and chronic infectious diseases. Here, we identified the homeobox protein Hhex as a negative regulator of Treg cells. The expression of Hhex was lower in Treg cells than in conventional T (Tconv) cells. Hhex expression was repressed in Treg cells by TGF-ß/Smad3 signaling. Retroviral overexpression of Hhex inhibited the differentiation of induced Treg (iTreg) cells and the stability of thymic Treg (tTreg) cells by significantly reducing Foxp3 expression. Moreover, Hhex-overexpressing Treg cells lost their immunosuppressive activity and failed to prevent colitis in a mouse model of inflammatory bowel disease (IBD). Hhex expression was increased; however, Foxp3 expression was decreased in Treg cells in a delayed-type hypersensitivity (DTH) reaction, a type I immune reaction. Hhex directly bound to the promoters of Foxp3 and other Treg signature genes, including Il2ra and Ctla4, and repressed their transactivation. The homeodomain and N-terminal repression domain of Hhex were critical for inhibiting Foxp3 and other Treg signature genes. Thus, Hhex plays an essential role in inhibiting Treg cell differentiation and function via inhibition of Foxp3.
Subject(s)
Forkhead Transcription Factors/metabolism , Homeodomain Proteins/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Transcription Factors/metabolism , Animals , CTLA-4 Antigen/metabolism , Cell Differentiation , Colitis/metabolism , Colitis/pathology , Disease Models, Animal , Forkhead Transcription Factors/genetics , Gene Expression Regulation , Homeodomain Proteins/genetics , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Interleukin-2 Receptor alpha Subunit/metabolism , Mice , Signal Transduction , Skin/pathology , Smad3 Protein/metabolism , Transcription Factors/genetics , Transforming Growth Factor beta/metabolismABSTRACT
Th9 cells preferentially produce IL-9 and participate in allergic responses and asthma. Differentiation of Th9 cells is induced by IL-4 and TGF-ß, and then the cells are amplified by OX40 signals. The transcription factors PU.1, IRF4, and BATF are required for Th9 differentiation. BATF3 is an AP-1 family transcription factor that is highly homologous to BATF; however, its role in Th9 cells is poorly defined. Here, we show that OX40 signaling induced the expression of Batf3 and that its overexpression in the presence or absence of OX40 signaling increased the expression of IL-9 in Th9 cells. BATF3 physically interacted with IRF4 and was bound to the Il9 locus. A transient reporter assay revealed that the BATF3-IRF4 complex induced Il9 promoter activity. BATF3 rescued Il9 expression and restored the capacity to induce the airway inflammation in Batf KO Th9 cells. Thus, BATF3 itself is sufficient for the induction of Th9 cell differentiation and can substitute for BATF during Th9 cell differentiation.
Subject(s)
Basic-Leucine Zipper Transcription Factors/metabolism , CD4-Positive T-Lymphocytes/metabolism , Interleukin-9/metabolism , Repressor Proteins/metabolism , Animals , Basic-Leucine Zipper Transcription Factors/genetics , Cell Differentiation/genetics , Cell Differentiation/physiology , Chromatin Immunoprecipitation , Enzyme-Linked Immunosorbent Assay , Immunoblotting , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Lung , Mice , Mice, Inbred C57BL , Mice, Knockout , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Repressor Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , Trans-Activators/genetics , Trans-Activators/metabolismABSTRACT
BACKGROUND: We evaluated the efficacy and safety of chemotherapy with S-1/CDDP for advanced and recurrent gastric cancer at Fuchu Hospital. METHODS: The participants were 24 patients treated at our hospital. S-1 was given orally at 80 mg/m/2 for days 1-21, and 60 mg/m2 of CDDP was administered on day 8, followed by a 2-week rest period, within a 5-week course. RESULTS: Results were rated as a partial response in 12 cases and a stable response in 4 cases. The response rate was 50% (12/24), and median survival time was 273 days. The total incidence of grade 3 or greater adverse reactions including leucopenia, neutropenia, anemia, general fatigue, and eruption, was 25% (6/24). CONCLUSION: The combination of S-1/CDDP therapy appears to be highly efficacious and safe and showed promise as a useful treatment strategy, even in an outpatient clinic.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/therapeutic use , Oxonic Acid/therapeutic use , Stomach Neoplasms/drug therapy , Tegafur/therapeutic use , Aged , Aged, 80 and over , Cisplatin/administration & dosage , Cisplatin/adverse effects , Combined Modality Therapy , Drug Combinations , Female , Humans , Male , Middle Aged , Oxonic Acid/administration & dosage , Oxonic Acid/adverse effects , Stomach Neoplasms/surgery , Survival Rate , Tegafur/administration & dosage , Tegafur/adverse effectsABSTRACT
This manuscript reviews the developments made in design and fabrication of piezoelectric microgenerators and presents a method for making a comparative study within various vibration energy harvesting mechanisms. Current generation vibration energy harvesters have power density in the range of 0.8 microW/mm3. The manuscript also reports our results on synthesis of barium titanate (BT) thin films for MEMS (micro-electromechanical systems) based energy harvester. BT sol-gel was synthesized by aqueous process using barium acetate and titanium bis (ammonium lacto) dihydroxide with PVP (Polyvinylpyrrolidone). After optimizing the annealing temperature and time, textured BT films with 600 nm thickness were obtained on (111) Pt/Ti/SiO2 wafer. A MEMS fabrication process flow was designed to produce microcantilever chips from BT films constituting 6 cantilevers connected in series with an interdigital electrode pattern. We also present some concepts for further improvement of the power density of vibration energy harvesters by incorporating 3-D structure, magnetoelectric material, and a multimodal scheme.
ABSTRACT
In this study, we report results on a piezoelectric- material-based mechanical energy-harvesting device that was fabricated by combining laser machining with microelectronics packaging technology. It was found that the laser-machining process did not have significant effect on the electrical properties of piezoelectric material. The fabricated device was tested in the low-frequency regime of 50 to 1000 Hz at constant force of 8 g (where g = 9.8 m/s(2)). The device was found to generate continuous power of 1.13 microW at 870 Hz across a 288.5 kOmega load with a power density of 301.3 microW/cm(3).
