scholarly journals Mapping Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells

2021 ◽  
Author(s):  
Ankitha Shetty ◽  
Santosh D. Bhosale ◽  
Subhash Kumar Tripathi ◽  
Tanja Buchacher ◽  
Rahul Biradar ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Affinity Purification ◽  
Mass Spectrometry Analysis ◽  
Binding Partners ◽  
Th17 Cell Differentiation

Dysregulated function of Th17 cells has implications in immunodeficiencies and autoimmune disorders. Th17 cell-differentiation is orchestrated by a complex network of transcription factors, including several members of the activator protein (AP-1) family. Among these, FOSL1 and FOSL2 influence the effector responses of Th17 cells. However, the molecular mechanisms underlying their functions are unclear, owing to the poorly characterized protein interaction networks of these factors. Here, we establish the first interactomes of FOSL1 and FOSL2 in human Th17 cells, using affinity purification–mass spectrometry analysis. In addition to the known JUN proteins, we identified several novel binding partners of FOSL1 and FOSL2. Gene ontology analysis found a major fraction of these interactors to be associated with RNA binding activity, which suggests new mechanistic links. Intriguingly, 29 proteins were found to share interactions with FOSL1 and FOSL2, and these included key regulators of Th17-fate. We further validated the binding partners identified in this study by using parallel reaction monitoring targeted mass spectrometry and other methods. Our study provides key insights into the interaction-based signaling mechanisms of FOSL1 and FOSL2 that potentially govern Th17 cell-differentiation and associated pathologies.

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.

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 Engineered Th17 cell differentiation using a photo-activatable immune modulator

2019 ◽  
Author(s):  
Bibudha Parasar ◽  
Pamela V. Chang
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Uv Light ◽  
T Cell Subsets ◽  
Light Illumination ◽  
Immune Modulator ◽  
On Demand ◽  
Th17 Cell Differentiation

AbstractT helper 17 (Th17) cells, an important subset of CD4+ T cells, help to eliminate extracellular infectious pathogens that have invaded our tissues. Despite the critical roles of Th17 cells in immunity, how the immune system regulates the production and maintenance of this cell type remains poorly understood. In particular, the plasticity of these cells, or their dynamic ability to trans-differentiate into other CD4+ T cell subsets, remains mostly uncharacterized. Here, we report a synthetic immunology approach using a photo-activatable immune modulator (PIM) to increase Th17 cell differentiation on demand with spatial and temporal precision to help elucidate this important and dynamic process. In this chemical strategy, we developed a latent agonist that, upon photochemical activation, releases a small-molecule ligand that targets the aryl hydrocarbon receptor (AhR) and ultimately induces Th17 cell differentiation. We used this chemical tool to control AhR activation with spatiotemporal precision within cells and to modulate Th17 cell differentiation on demand by using UV light illumination. We envision that this approach will enable an understanding of the dynamic functions and behaviors of Th17 cells in vivo during immune responses and in mouse models of inflammatory disease.

scholarly journals PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Luis Eduardo Alves Damasceno ◽  
Douglas Silva Prado ◽  
Flavio Protasio Veras ◽  
Miriam M. Fonseca ◽  
Juliana E. Toller-Kawahisa ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Glycolytic Enzyme ◽  
Metabolic Reprogramming ◽  
Fine Tuning ◽  
Autoimmune Inflammation ◽  
Th17 Cell Differentiation ◽  
Key Factor

Th17 cell differentiation and pathogenicity depend on metabolic reprogramming inducing shifts toward glycolysis. Here, we show that the pyruvate kinase M2 (PKM2), a glycolytic enzyme required for cancer cell proliferation and tumor progression, is a key factor mediating Th17 cell differentiation and autoimmune inflammation. We found that PKM2 is highly expressed throughout the differentiation of Th17 cells in vitro and during experimental autoimmune encephalomyelitis (EAE) development. Strikingly, PKM2 is not required for the metabolic reprogramming and proliferative capacity of Th17 cells. However, T cell–specific PKM2 deletion impairs Th17 cell differentiation and ameliorates symptoms of EAE by decreasing Th17 cell–mediated inflammation and demyelination. Mechanistically, PKM2 translocates into the nucleus and interacts with STAT3, enhancing its activation and thereby increasing Th17 cell differentiation. Thus, PKM2 acts as a critical nonmetabolic regulator that fine-tunes Th17 cell differentiation and function in autoimmune-mediated inflammation.

scholarly journals Mycobacterium tuberculosis RpfE-Induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation

2021 ◽  
Vol 22 (14) ◽  
pp. 7535
Author(s):  
Hye-Soo Park ◽  
Seunga Choi ◽  
Yong-Woo Back ◽  
Kang-In Lee ◽  
Han-Gyu Choi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Cell Differentiation ◽  
Prostaglandin E2 ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Bacterial Load ◽  
Cell Responses ◽  
Ep4 Receptor ◽  
Th17 Cell Differentiation

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.

scholarly journals IL-17A and Th17 Cells in Lung Inflammation: An Update on the Role of Th17 Cell Differentiation and IL-17R Signaling in Host Defense against Infection

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Hsing-Chuan Tsai ◽  
Sharlene Velichko ◽  
Li-Yin Hung ◽  
Reen Wu
Keyword(s):  
Cell Differentiation ◽  
Host Defense ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Critical Role ◽  
Klebsiella Pneumonia ◽  
Antimicrobial Proteins ◽  
Cytokines And Chemokines ◽  
Th17 Cell Differentiation

The significance of Th17 cells and interleukin- (IL-)17A signaling in host defense and disease development has been demonstrated in various infection and autoimmune models. Numerous studies have indicated that Th17 cells and its signature cytokine IL-17A are critical to the airway’s immune response against various bacteria and fungal infection. Cytokines such as IL-23, which are involved in Th17 differentiation, play a critical role in controllingKlebsiella pneumonia(K. pneumonia) infection. IL-17A acts on nonimmune cells in infected tissues to strengthen innate immunity by inducing the expression of antimicrobial proteins, cytokines, and chemokines. Mice deficient in IL-17 receptor (IL-17R) expression are susceptible to infection by various pathogens. In this review, we summarize the recent advances in unraveling the mechanism behind Th17 cell differentiation, IL-17A/IL-17R signaling, and also the importance of IL-17A in pulmonary infection.

scholarly journals IL-1 Receptor Blockade Alleviates Graft-versus-Host Disease through Downregulation of an Interleukin-1β-Dependent Glycolytic Pathway in Th17 Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Min-Jung Park ◽  
Seung Hoon Lee ◽  
Sung-Hee Lee ◽  
Eun-Jung Lee ◽  
Eun-Kyung Kim ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
T Cell Response ◽  
Host Disease ◽  
Graft Versus Host ◽  
Th17 Cell Differentiation

T helper (Th) 17 cells are a subset of Th cells expressing interleukin- (IL-) 17 and initiating an inflammatory response in autoimmune diseases. Graft-versus-host disease (GVHD) is an immune inflammatory disease caused by interactions between the adaptive immunity of donor and recipient. The Th17 lineage exhibits proinflammatory activity and is believed to be a central player in GVHD. IL-1 performs a key function in immune responses and induces development of Th17 cells. Here, we show that blockade of IL-1 signaling suppresses Th17 cell differentiation and alleviates GVHD severity. We hypothesized that the IL-1 receptor antagonist (IL-1Ra) would suppress Th17 cell differentiationin vitrovia inhibition of glycolysis-related genes. Blockade of IL-1 using IL-1Ra downregulated Th17 cell differentiation, an alloreactive T cell response, and expression of genes of the glycolysis pathway. Severity of GVHD was reduced in mice with a transplant of IL-Ra-treated cells, in comparison with control mice. To clarify the mechanisms via which IL-1Ra exerts the therapeutic effect, we demonstratedin vivothat IL-1Ra decreased the proportion of Th17 cells, increased the proportion of FoxP3-expressing T regulatory (Treg) cells, and inhibited expression of glycolysis-related genes and suppressed Th17 cell development and B-cell activation. These results suggest that blockade of IL-1 signaling ameliorates GVHD via suppression of excessive T cell-related inflammation.

scholarly journals MBD2 Regulates Th17 Cell Differentiation and Experimental Severe Asthma by Affecting IRF4 Expression

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Aijun Jia ◽  
Yueling Wang ◽  
Wenjin Sun ◽  
Bing Xiao ◽  
Yan Wei ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Protein Expression ◽  
Severe Asthma ◽  
Epigenetic Regulation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Neutrophil Infiltration ◽  
Neutrophil Granulocyte ◽  
Th17 Cell Differentiation ◽  
Significant Difference

Th17 cells and IL-17 participate in airway neutrophil infiltration characteristics in the pathogenesis of severe asthma. Methyl-CpG binding domain protein 2 (MBD2) expression increased in CD4+ T cells in peripheral blood samples of asthma patients. However, little is known about that epigenetic regulation of MBD2 in both immunological pathogenesis of experimental severe asthma and CD4+ T cell differentiation. Here, we established a neutrophil-predominant severe asthma model, which was characterized by airway hyperresponsiveness (AHR), BALF neutrophil granulocyte (NEU) increase, higher NEU and IL-17 protein levels, and more Th17 cell differentiation. In the model, MBD2 and IRF4 protein expression increased in the lung and spleen cells. Under overexpression or silencing of the MBD2 and IRF4 gene, the differentiation of Th17 cells and IL-17 secretion showed positive changes. IRF4 protein expression showed a positive change with overexpression or silencing of the MBD2 gene, whereas there was no significant difference in the expression of MBD2 under overexpression or silencing of the IRF4 gene. These data provide novel insights into epigenetic regulation of severe asthma.

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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