scholarly journals ADAM9 enhances Th17 cell differentiation and autoimmunity by activating TGF-β1

2021 ◽  
Vol 118 (18) ◽  
pp. e2023230118
Author(s):  
Masataka Umeda ◽  
Nobuya Yoshida ◽  
Ryo Hisada ◽  
Catalina Burbano ◽  
Seo Yeon K. Orite ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Growth Factor ◽  
Lupus Erythematosus ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Th17 Cell Differentiation ◽  
Adam Family

The a disintegrin and metalloproteinase (ADAM) family of proteinases alter the extracellular environment and are involved in the development of T cells and autoimmunity. The role of ADAM family members in Th17 cell differentiation is unknown. We identified ADAM9 to be specifically expressed and to promote Th17 differentiation. Mechanistically, we found that ADAM9 cleaved the latency-associated peptide to produce bioactive transforming growth factor β1, which promoted SMAD2/3 phosphorylation and activation. A transcription factor inducible cAMP early repressor was found to bind directly to the ADAM9 promoter and to promote its transcription. Adam9-deficient mice displayed mitigated experimental autoimmune encephalomyelitis, and transfer of Adam9-deficient myelin oligodendrocyte globulin-specific T cells into Rag1−/− mice failed to induce disease. At the translational level, an increased abundance of ADAM9 levels was observed in CD4+ T cells from patients with systemic lupus erythematosus, and ADAM9 gene deletion in lupus primary CD4+ T cells clearly attenuated their ability to differentiate into Th17 cells. These findings revealed that ADAM9 as a proteinase provides Th17 cells with an ability to activate transforming growth factor β1 and accelerates its differentiation, resulting in aberrant autoimmunity.

scholarly journals Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation

2009 ◽  
Vol 206 (11) ◽  
pp. 2407-2416 ◽  
Author(s):  
Jyoti Das ◽  
Guangwen Ren ◽  
Liying Zhang ◽  
Arthur I. Roberts ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Th2 Cells ◽  
Th17 Cell Differentiation ◽  
Th1 And Th2

Interleukin (IL)-17–producing T helper (Th17) cells play a critical role in the pathophysiology of several autoimmune disorders. The differentiation of Th17 cells requires the simultaneous presence of an unusual combination of cytokines: IL-6, a proinflammatory cytokine, and transforming growth factor (TGF) β, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-β exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor γt, a Th17-specific transcription factor. Interestingly, in Stat-6−/−T-bet−/− mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whereas TGF-β had no effect, suggesting that TGF-β is dispensable for Th17 cell development. Consequently, BALB/c Stat-6−/−T-bet−/− mice, but not wild-type BALB/c mice, were highly susceptible to the development of experimental autoimmune encephalomyelitis, which could be blocked by anti–IL-17 antibodies but not by anti–TGF-β antibodies. Collectively, these data provide evidence that TGF-β is not directly required for the molecular orchestration of Th17 cell differentiation.

scholarly journals Autocrine Transforming Growth Factor-β1 Promotes In Vivo Th17 Cell Differentiation

Immunity ◽  
2011 ◽  
Vol 34 (3) ◽  
pp. 396-408 ◽  
Author(s):  
Ilona Gutcher ◽  
Moses K. Donkor ◽  
Qian Ma ◽  
Alexander Y. Rudensky ◽  
Richard A. Flavell ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Th17 Cell Differentiation

Hydroxychloroquine Inhibits the Differentiation of Th17 Cells in Systemic Lupus Erythematosus

2018 ◽  
Vol 45 (6) ◽  
pp. 818-826 ◽  
Author(s):  
Ji Yang ◽  
Xue Yang ◽  
Jie Yang ◽  
Ming Li
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Lupus Erythematosus ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Systemic Lupus ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Th17 Cell Differentiation

Objective.Hydroxychloroquine (HCQ) is a commonly used medicine for the treatment of systemic lupus erythematosus (SLE), and Th17 cells are closely related to the pathogenesis of SLE. However, the role and mechanism of HCQ on Th17 cell differentiation in SLE is not clearly understood. Here, we investigate the effect of HCQ on Th17 cell differentiation bothin vitroand in patients with SLE.Methods.Twenty-five patients with SLE were divided into 2 treatment groups: prednisone alone and HCQ plus prednisone. Interleukin 17 (IL-17) expression was analyzed by ELISA and real-time (RT)-PCR. Th17 were measured in patients with SLE by flow cytometry before and after HCQ treatment.In vitro, naive T cells were cultured in Th17-inducing conditions with or without HCQ. Cell differentiation and IL-17 expression were analyzed. Finally, transcriptome sequencing identified differential gene expression between naive T cells and induced Th17 cells.Results.In patients, HCQ plus prednisone treatment inhibited IL-17 production, gene expression, and Th17 cell differentiation.In vitro, HCQ inhibited Th17 cell proliferation and differentiation, as well as IL-17 production. Five microRNA were significantly different in Th17 cells compared with naive T cells, and HCQ treatment reversed this effect.In vivo, microRNA-590 (miR-590) was verified and was significantly decreased in Th17 cells, compared with naive T cells from lupus-prone mice. Moreover, miR-590 was increased in patients treated with HCQ plus prednisone.Conclusion.HCQ inhibited Th17 cell differentiation and IL-17 production bothin vitroand in patients with SLE. Our study provides additional evidence for HCQ as a treatment for SLE.

Malignant B Cells Skew the Balance between Treg Cell and TH17 Cell Differentiation in B-Cell Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1347-1347
Author(s):  
Zhi-Zhang Yang ◽  
Anne J. Novak ◽  
Thomas E. Witzig ◽  
Stephen M. Ansell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Th17 Cell Differentiation

Abstract Numerous clinical therapies have attempted to modulate tumor cell immunity, but for the most part, have proven unsuccessful. The inability to produce or augment an effective immune response is due in part to regulatory T (Treg) cells, which inhibit CD4 and CD8 T cell function. Our group has recently shown that Treg cell numbers are elevated in NHL tumors and that NHL B cells induce the development of Treg cells thereby inhibiting anti-tumor responses. The ability of NHL B cells to direct the cellular composition of their microenvironment is critical to our understanding of tumor immunity and we therefore wanted to determine if NHL B cells also directed the expansion or reduction of other T cell populations. IL-17-secreting CD4+ T cells (TH17), a newly characterized CD4+ T helper cell lineage, promote inflammation and play an important role in autoimmune disease. IL-17 has been shown to inhibit tumor cell growth suggesting a potential role for TH17 cells in anti-tumor immunity. We therefore set out to determine if TH17 cells were present in NHL tumors and whether or not their numbers were regulated by NHL B cells. Using unsorted mononuclear cells from malignant lymph nodes, we were unable to detect IL-17 expression in resting CD4+ T cells or CD4+ T cells activated with PMA/Ionomycin stimulation (less than 1%). However, IL-17-secreting CD4+ T cells could be detected in significant numbers in inflammatory tonsil and normal PBMCs. Interestingly, depletion of CD19+ NHL B cells from mononuclear cells obtained from patient biopsies resulted in detection of a clear population of IL-17-secreting CD4+ T cells (5%). These results suggest that NHL B cells suppress TH17 cell differentiation. The frequency of IL-17-secreting CD4+ T cells could not be further enhanced by the addition of exogenous TGF-b and IL-6, a cytokine combination favoring for TH17 differentiation, suggesting a further impairment of TH17 cell differentiation in the tumor microenvironment. In contrast, Foxp3 expression could be detected in resting CD4+ T cells (30%) and could be induced in CD4+CD25−Foxp3− T cells activated with TCR stimulation (28%). Contrary to the inhibition of TGF-b-mediated TH17 differentiation, Foxp3 expression could be dramatically upregulated by TGF-b in intratumoral CD4+ T cells (35%). In addition, lymphoma B cells strongly enhanced Foxp3 expression in intratumoral CD4+CD25−Foxp3−. Furthermore, when added together, the frequency of Foxp3+ T cells and Foxp3-inducible cells reached up to 60% of CD4+ T cells in tumor microenvironment of B-cell NHL. These findings suggest that the balance of effector TH17 cells and inhibitory Treg cells is disrupted in B-cell NHL and significantly favors the development of inhibitory Treg cells. Our data indicate that lymphoma B cells are key factor in regulating differentiation of intratumoral CD4+ T cells toward inhibitory CD4+ T cells.

scholarly journals SKI Expression Suppresses Pathogenic Th17 Cell Response and Mitigates Experimental Autoimmune Encephalomyelitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ping Li ◽  
Zengli Guo ◽  
Yisong Y. Wan
Keyword(s):  
Cell Differentiation ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Transfer Model ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Cell Differentiation ◽  
Experimental Autoimmune

Pathogenic Th17 cells are critically involved in many autoimmune diseases, while non-pathogenic Th17 cells are more immune regulatory. Understanding the mechanisms of the induction and maintenance of pathogenic Th17 cells will benefit the development of therapeutic treatments of related diseases. We have shown that the transforming growth factor-β (TGFβ) induced SKI degradation and dissociation from Smad4 complex is a prerequisite for TGFβ-induced Th17 cell differentiation. However, it is unclear whether and how SKI regulates pathogenic Th17 differentiation, which does not require TGFβ cytokine. Here we showed that SKI expression was downregulated during pathogenic Th17 cell differentiation and the ectopic expression of SKI abrogated the differentiation of pathogenic Th17 cells. Functionally, using a knock-in mouse model, we found ectopic SKI expression specifically in T cells prevented myelin oligodendrocyte glycoprotein peptide (MOG33–55) induced experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis. We further revealed that induced SKI expression in already differentiated pathogenic Th17 cells reduced the maintenance of Th17 program and ameliorated EAE in an adoptive T cell transfer model. Therefore, our study provides valuable insights of targeting SKI to modulate pathogenic Th17 cell function and treat Th17-related diseases.

scholarly journals Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation

2009 ◽  
Vol 206 (13) ◽  
pp. 3157-3157 ◽  
Author(s):  
Jyoti Das ◽  
Guangwen Ren ◽  
Liying Zhang ◽  
Arthur I. Roberts ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Th17 Cell Differentiation

scholarly journals Correlation of Interleukin-17-Producing Effector Memory T Cells and CD4+CD25+Foxp3 Regulatory T Cells with the Phosphate Levels in Chronic Hemodialysis Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Cheng-Lin Lang ◽  
Min-Hui Wang ◽  
Kuan-Yu Hung ◽  
Sung-Hao Hsu ◽  
Chih-Kang Chiang ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Treg Cells ◽  
Chronic Hemodialysis ◽  
T Cell Differentiation ◽  
Effector Memory ◽  
Interleukin 17 ◽  
Th17 Cell Differentiation

Background and Objectives. Hyperparathyroidism and hyperphosphatemia contribute to the inflammatory effects in chronic hemodialysis (HD) patients. Interleukin-17-producingCD4+effector memory T (Th17) cells and CD4+CD25+Foxp3 regulatory T (Treg) cells both play critical roles in immune activation and inflammation. We investigated the relationship between the Treg and Th17 cells and the phosphate level in chronic HD patients.Methods. 105 patients aged ≥35 years on chronic HD over 3 months were enrolled. The peripheral blood mononuclear cells were collected, cultured, and stimulated by phytohemagglutinin-L, phorbol myristate acetate, and ionomycin at different time points for T cell differentiation.Results. The T cell differentiation was as follows: Th17 cells (mean ± standard deviation (SD): 25.61% ± 10.2%) and Treg cells (8.45% ± 4.3%). The Th17 cell differentiation was positively correlated with the phosphate and albumin levels and negatively correlated with age. The Treg cell differentiation was negatively correlated with albumin level and age. In the nondiabetes group (n=53), the Th17 cell differentiation was predominantly correlated with the phosphate and iPTH (intact parathyroid hormone) levels as well as the dialysis vintage.Conclusion. Higher phosphate and iPTH levels and longer dialysis duration may increase Th17 cell differentiation, especially in the nondiabetic chronic HD patients.

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