scholarly journals The Fate of Th17 Cells is Shaped by Epigenetic Modifications and Remodeled by the Tumor Microenvironment

2020 ◽  
Vol 21 (5) ◽  
pp. 1673 ◽  
Author(s):  
Elodie Renaude ◽  
Marie Kroemer ◽  
Romain Loyon ◽  
Delphine Binda ◽  
Christophe Borg ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
Transcription Factor ◽  
Tumor Microenvironment ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Epigenetic Modifications ◽  
High Plasticity ◽  
Th17 Cell Differentiation ◽  
Promising Treatment

Th17 cells represent a subset of CD4+ T cells characterized by the master transcription factor RORγt and the production of IL-17. Epigenetic modifications such as post-translational histone modifications and DNA methylation play a key role in Th17 cell differentiation and high plasticity. Th17 cells are highly recruited in many types of cancer and can be associated with good or bad prognosis. Here, we will review the remodeling of the epigenome induced by the tumor microenvironment, which may explain Th17 cell predominance. We will also discuss the promising treatment perspectives of molecules targeting epigenetic enzymes to remodel a Th17-enriched tumor microenvironment.

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 Pro-Tumor and Anti-Tumor Functions of IL-17 and of TH17 Cells in Tumor Microenvironment

2016 ◽  
Vol 43 (2) ◽  
pp. 68-79 ◽  
Author(s):  
M. Gulubova ◽  
J. Ananiev ◽  
M. Ignatova ◽  
K. Halacheva
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Tumor Microenvironment ◽  
Th17 Cells ◽  
T Helper ◽  
Main Attention ◽  
Tumor Microenvironments ◽  
Th17 Cell Differentiation ◽  
Regulatory Functions

Summary The current review reveals the seven subclasses of CD4+ T helper cells, i.e. Th1, Th2, Th9, Th17, Th22, regulatory T cells and Tfh, the cytokines produced by them and their role in tumor microenvironment. Main attention was paid to IL-17 and Th17 cells. IL-17-producing cells were described, among which were Treg17 cells and Tc17 cells. The transcription factors, engaged in the activation of Th17 cell differentiation were reviewed. It was shown that Th17 cells might possess regulatory functions in tumor microenvironments that directs toward immunosuppression. The reciprocity between Treg and Th17 cells is realized when the production of a large amount of TGF-β in tumors causes Treg cell differentiation, and the addition of IL-6 shifts the differentiation of naïve T cells to Th17 cells. The main pro-tumor role of IL-17 is the promotion of tumor angiogenesis through stimulation of fibroblasts and endothelial cells. The antitumor functions of IL-17 are associated with enhancement of cytotoxic activity of tumor specific CTL cells and with angiogenesis that provide channels through which immune cells might invade tumor and promote antitumor immunity.

scholarly journals HuR Plays a Positive Role to Strengthen the Signaling Pathways of CD4+ T Cell Activation and Th17 Cell Differentiation

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Shiguang Yu ◽  
Morgan Tripod ◽  
Ulus Atasoy ◽  
Jing Chen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Th17 Cell Differentiation

After antigen and/or different cytokine stimulation, CD4+ T cells activated and differentiated into distinct T helper (Th) cells via differential T cell signaling pathways. Transcriptional regulation of the activation and differentiation of naïve CD4+ T cells into distinct lineage Th cells such as Th17 cells has been fully studied. However, the role of RNA-binding protein HuR in the signaling pathways of their activation and differentiation has not been well characterized. Here, we used HuR conditional knockout (HuR KO) CD4+ T cells to study mechanisms underlying HuR regulation of T cell activation and differentiation through distinct signaling pathways. Our work showed that, mechanistically, HuR positively promoted CD3g expression by binding its mRNA and enhanced the expression of downstream adaptor Zap70 and Malt1 in activated CD4+ T cells. Compared to WT Th0 cells, HuR KO Th0 cells with reduced Bcl-2 expression are much more susceptible to apoptosis than WT Th0 cells. We also found that HuR stabilized IL-6Rα mRNA and promoted IL-6Rα protein expression, thereby upregulating its downstream phosphorylation of Jak1 and Stat3 and increased level of phosphorylation of IκBα to facilitate Th17 cell differentiation. However, knockout of HuR increased IL-22 production in Th17 cells, which was due to HuR deficiency in reducing IL-22 transcription repressor c-Maf expression. These results highlight the importance of HuR in TCR signaling and IL-6/IL-6R axis driving naïve CD4+ T cell activation and differentiation into Th17 cells.

scholarly journals Immunopathogenesis of IBD: Batf as a Key Driver of Disease Activity

2016 ◽  
Vol 34 (Suppl. 1) ◽  
pp. 40-47 ◽  
Author(s):  
Kai Hildner ◽  
Elise Punkenburg ◽  
Benjamin Abendroth ◽  
Markus F. Neurath
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Immune System ◽  
T Cell ◽  
Epithelial Cell ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Intestinal Epithelial Cell ◽  
Intestinal Epithelial ◽  
Immune Mediated

Background: Inflammatory bowel diseases (IBDs) represent a group of chronic immune-mediated disorders that are influenced by a genetic predisposition and additional environmental triggers. Genome-wide association studies strongly implicate that a number of immune system-related genetic variations are critically contributing to the initiation and promotion of intestinal inflammation. Especially the identification of the strong association of a series of single nucleotide polymorphisms including interleukin (IL)-23R, CCR6, signal transducer and activator of transcription 3 (Stat3) and Stat4 with IBD susceptibility point at a critical involvement of T cells and especially of IL-17a-producing Th17 cells in the immune pathogenesis of IBD. In line with this hypothesis, a series of preclinical studies have unequivocally established that T cells are key drivers of immune-mediated colitis. Interestingly, especially Th17 cells were identified to be highly prevalent in inflamed IBD tissues, a finding that seems to be functionally relevant as genetic inactivation studies in the mouse resulted in almost complete suppression of colitis development. Key Messages: While targeting Th17 cell differentiation regulating transcription factors, as retinoic acid-related orphan receptor gamma t (RORγt) is effective in preventing murine colitis, one concern of drugs targeting RORγt in a clinical setting represents the large body of murine data unambiguously demonstrating that additional pathways within and outside the immune system are equally RORγt-dependent increasing the risk of undesirable side effects. The AP1 transcription factor Batf (B cell-activating transcription factor) appears to exclusively regulate pathways within lymphocytes. Importantly, Batf represents a central regulator of Th17 cell development and is strongly upregulated within IBD-affected tissues. Employing 2 acute colitis models, we demonstrate in this study that Batf-expressing T cells are critical drivers of T cell-mediated colitis while in contrast to Stat3 loss of Batf does not affect intestinal epithelial cell homeostasis ex vivo. Conclusions: Targeting Batf in IBD emerges as an attractive therapeutic approach disabling colitogenic T cell activities while sparing off-target effects in the intestinal epithelial cell compartment.

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.

scholarly journals Tumor exosome promotes Th17 cell differentiation by transmitting the lncRNA CRNDE-h in colorectal cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Junfeng Sun ◽  
Haowei Jia ◽  
Xingqi Bao ◽  
Yue Wu ◽  
Tianyu Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
T Helper 17 ◽  
Th17 Cell Differentiation

AbstractThe T helper 17 (Th17) cells in tumor microenvironment play an important role in colorectal cancer (CRC) progression. This study investigated the mechanism of Th17 cell differentiation in CRC with a focus on the role of tumor exosome-transmitted long noncoding RNA (lncRNA). Exosomes were isolated from the CRC cells and serum of CRC patients. The role and mechanism of the lncRNA CRNDE-h transmitted by CRC exosomes in Th17 cell differentiation were assessed by using various molecular biological methods. The serum exosomal CRNDE-h level was positively correlated with the proportion of Th17 cells in the tumor-infiltrating T cells in CRC patients. CRC exosomes contained abundant CRNDE-h and transmitted them to CD4+ T cells to increase the Th17 cell proportion, RORγt expression, and IL-17 promoter activity. The underlying mechanism is that, CRNDE-h bound to the PPXY motif of RORγt and impeded the ubiquitination and degradation of RORγt by inhibiting its binding with the E3 ubiquitin ligase Itch. The in vivo experiments confirmed that the targeted silence of CRNDE-h in CD4+ T cells attenuated the CRC tumor growth in mice. The present findings demonstrated that the tumor exosome transmitted CRNDE-h promoted Th17 cell differentiation by inhibiting the Itch-mediated ubiquitination and degradation of RORγt in CRC, expanding our understanding of Th17 cell differentiation in CRC.

scholarly journals CD147 Is Essential for the Development of Psoriasis via the Induction of Th17 Cell Differentiation

2021 ◽  
Vol 23 (1) ◽  
pp. 177
Author(s):  
Aoi Okubo ◽  
Youhei Uchida ◽  
Yuko Higashi ◽  
Takuya Sato ◽  
Youichi Ogawa ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Transmembrane Protein ◽  
Immunoglobulin Superfamily ◽  
Monocarboxylate Transporters ◽  
Th17 Cell Differentiation

Th17 cells play an important role in psoriasis. The differentiation of naïve CD4+ T cells into Th17 cells depends on glycolysis as the energy source. CD147/basigin, an integral transmembrane protein belonging to the immunoglobulin superfamily, regulates glycolysis in association with monocarboxylate transporters (MCTs)-1 and -4 in cancer cells and T cells. We examined whether CD147/basigin is involved in the pathogenesis of psoriasis in humans and psoriasis-model mice. The serum level of CD147 was increased in patients with psoriasis, and the expression of CD147 and MCT-1 was elevated in their dermal CD4+ RORγt+ T cells. In vitro, the potential of naïve CD4+ T cells to differentiate into Th17 cells was abrogated in CD147−/− T cells. Imiquimod (IMQ)-induced psoriatic dermatitis was significantly milder in CD147−/− mice and bone marrow chimeric mice lacking CD147 in the hematopoietic cells of myeloid lineage. These findings demonstrate that CD147 is essential for the development of psoriasis via the induction of Th17 cell differentiation.

scholarly journals Regulating human Th17 cells via differential expression of IL-1 receptor

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 530-540 ◽  
Author(s):  
Won-Woo Lee ◽  
Seong Wook Kang ◽  
Jihoon Choi ◽  
Seung-Hyun Lee ◽  
Kamini Shah ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Differential Expression ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Receptor Expression ◽  
Th17 Cell Differentiation ◽  
Memory Cd4 T Cells

Abstract In humans, interleukin-1β (IL-1β) has been suggested as an essential cytokine for developing IL-17– or IL-17A–producing CD4+ T helper 17 (Th17) cells. However, little is known about the relationship of IL-1 receptor expression and Th17 cell differentiation. We report here the presence of 2 distinct CD4+ T-cell populations with and without expression of IL-1RI that correlates with the capacity to produce IL-17 in naive and memory CD4+ T cells of human peripheral blood. IL-1RI+ memory CD4+ T cells had increased gene expression of IL17, RORC, and IRF4 even before T-cell receptor triggering, indicating that the effect of IL-1β is programmed in these cells via IL-1RI. Although CD4+ T cells from umbilical cord blood did not express IL-1RI, the cytokines IL-7, IL-15, and transforming growth factor-β (TGF-β) up-regulated IL-1RI expression on naive CD4+ T cells, suggesting that IL-1RI+ naive CD4+ T cells develop in periphery. Furthermore, IL-17 production from the cytokine-treated naive CD4+ T cells was induced by IL-1β and this induction was blocked by IL-1R antagonist. These results indicate that human Th17 cell differentiation is regulated via differential expression of IL-1RI, which is controlled by IL-7 and IL-15.

Antrodia cinnamomea Extract Inhibits Th17 Cell Differentiation and Ameliorates Imiquimod-Induced Psoriasiform Skin Inflammation

2015 ◽  
Vol 43 (07) ◽  
pp. 1401-1417 ◽  
Author(s):  
Ming-Han Li ◽  
Hsin-Chieh Wu ◽  
Hsin-Jan Yao ◽  
Chi-Chen Lin ◽  
Shu-Fang Wen ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Critical Role ◽  
Skin Inflammation ◽  
Therapeutic Effects ◽  
Antrodia Cinnamomea ◽  
Th17 Cell Differentiation ◽  
Stat3 Phosphorylation

Antrodia cinnamomea (A. cinnamomea) is a Chinese medicinal herb that possesses a broad range of bioactivities, including anti-inflammation. Given that the proinflammatory cytokine IL-17 plays a critical role in the pathogenesis of autoimmune diseases, we investigated whether A. cinnamomea could inhibit the development of Th17 cells, the main producer of IL-17, and exhibit therapeutic effects on an animal model of psoriasis. We found that A. cinnamomea extract (AC) inhibited the differentiation of Th17 cells as well as the production of IL-17A, IL-21, and IL-22 from these cells. This effect was associated with the inhibition of STAT3 phosphorylation and ROR[Formula: see text]t expression. Notably, the oral administration of AC reduced psoriasis-like inflammation in imiquimod-mediated dermal damage, repressed the expression of IL-17A, IL-22, and TNF-[Formula: see text] in skin lesions, and decreased the infiltration of CD4[Formula: see text] T cells, CD8[Formula: see text] T cells, and neutrophils into the dermis. Finally, serum levels of IL-17A were decreased in AC-treated mice with psoriasis-like skin inflammation. Taken together, these findings indicate that AC inhibits Th17 cell differentiation, suggesting a role for A. cinnamomea in the treatment of psoriasis and other Th17 cell-mediated inflammatory diseases.

scholarly journals Elevated IL-6R on CD4+ T cells promotes IL-6 driven Th17 cell responses in patients with T1R leprosy reactions

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chaman Saini ◽  
Rupesh K. Srivastava ◽  
Mohd. Tarique ◽  
Santosh Kurra ◽  
Neena Khanna ◽  
...  
Keyword(s):  
T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Treatment Strategies ◽  
Vital Role ◽  
Dependent Manner ◽  
Leprosy Reactions ◽  
Th17 Cell Differentiation ◽  
Leprosy Patients ◽  
First Time

Abstract Th17 cells play vital role during pathogenesis of leprosy reactions. Previously, we have reported that IL-23 is involved in Th17 cells differentiation. Subsequently, our group also showed that IL-6 induces Th17 cell differentiation along with TGF-β in leprosy reactions. Here, we next asked the question that whether IL-6 or IL-23 induced Th17 cells are different in nature? In this study, Type 1 Reactions (T1R) showed significantly (p < 0.001) higher percentage of IL-17A producing CD4+IL6R+ T cells as compared to non-reaction (NR) patients. Furthermore, recombinant IL-6, IL-23 and TGF-β promoted IL-17A secretion by CD4+IL6R+ T cells. Subsequently, IL-6R and IL-23R blocking experiments showed significantly (p < 0.002) down regulated IL-17A in T1R reaction as compared to NR leprosy patients. The present study for the first time establishes that pathogenic Th17 cells produce IL-17 in an IL-6 dependent manner in leprosy T1R reactions. Thus, present approaches that specifically target Th17 cells and/or the cytokines that promote their development, such as IL-6, TGF-β and IL-23A may provide more focused treatment strategies for the management of Mycobacterium leprae and its reactions.

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