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https://www.readbyqxmd.com/read/28531229/protein-kinase-c-theta-is-dispensable-for-suppression-mediated-by-cd25-cd4-regulatory-t-cells
#1
Kerstin Siegmund, Nikolaus Thuille, Katarzyna Wachowicz, Natascha Hermann-Kleiter, Gottfried Baier
The activation of conventional T cells upon T cell receptor stimulation critically depends on protein kinase C theta (PKCθ). However, its role in regulatory T (Treg) cell function has yet to be fully elucidated. Using siRNA or the potent and PKC family-selective pharmacological inhibitor AEB071, we could show that murine Treg-mediated suppression in vitro is independent of PKCθ function. Likewise, Treg cells of PKCθ-deficient mice were fully functional, showing a similar suppressive activity as wild-type CD25+CD4+ T cells in an in vitro suppression assay...
2017: PloS One
https://www.readbyqxmd.com/read/28503202/stabilization-of-foxp3-expression-by-crispr-dcas9-based-epigenome-editing-in-mouse-primary-t-cells
#2
Masahiro Okada, Mitsuhiro Kanamori, Kazue Someya, Hiroko Nakatsukasa, Akihiko Yoshimura
BACKGROUND: Epigenome editing is expected to manipulate transcription and cell fates and to elucidate the gene expression mechanisms in various cell types. For functional epigenome editing, assessing the chromatin context-dependent activity of artificial epigenetic modifier is required. RESULTS: In this study, we applied clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9-based epigenome editing to mouse primary T cells, focusing on the Forkhead box P3 (Foxp3) gene locus, a master transcription factor of regulatory T cells (Tregs)...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28470889/in-vitro-induction-of-human-regulatory-t-cells-itregs-using-conditions-of-low-tryptophan-plus-kynurenines
#3
K L Hippen, R S O'Connor, A M Lemire, A Saha, E A Hanse, N C Tennis, S C Merkel, A Kelekar, J L Riley, B L Levine, C H June, L S Kean, M L MacMillan, J S Miller, J E Wagner, D H Munn, B R Blazar
Thymic regulatory T cells (tTreg) or induced Tregs (iTregs) suppress murine acute graft-versus-host disease (GVHD). Previously we demonstrated that plasmacytoid dendritic cell (pDC) indoleamine 2,3-dioxygenase (IDO) fosters the in vitro development of human iTregs via tryptophan depletion and kynurenine (Kyn) metabolites. We now show that stimulation of naïve CD4+ T cells in low tryptophan (Low Trp) plus Kyn supports human iTreg generation. In vitro, low Trp+Kyn iTreg and tTregs potently suppress Teffector cell proliferation equivalently but are phenotypically distinct...
May 4, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28467968/transcription-factor-c-rel-is-indispensable-for-generation-of-thymic-but-not-of-peripheral-foxp3-regulatory-t-cells
#4
Maik Luu, Elena Jenike, Niyati Vachharajani, Alexander Visekruna
The transcription factor c-Rel has been shown to be crucial for development of regulatory T cells (Tregs). Recent studies have reported that the expression of transcription factor Helios in Foxp3+ Tregs correlates with thymic origin of these cells (tTregs). Notably, we found that only the Helios+Foxp3+ Treg cell population was substantially reduced in c-Rel deficient mice. In contrast to a defective tTreg development, we observed an expansion of mucosal Tregs during the induction of acute colitis in rel-/- mice...
April 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408906/cellular-and-molecular-dynamics-of-th17-differentiation-and-its-developmental-plasticity-in-the-intestinal-immune-response
#5
REVIEW
Suniti Bhaumik, Rajatava Basu
After emerging from the thymus, naive CD4 T cells circulate through secondary lymphoid tissues, including gut-associated lymphoid tissue of the intestine. The activation of naïve CD4 T cells by antigen-presenting cells offering cognate antigen initiate differentiation programs that lead to the development of highly specialized T helper (Th) cell lineages. Although initially believed that developmental programing of effector T cells such as T helper 1 (Th1) or T helper 2 (Th2) resulted in irreversible commitment to a fixed fate, subsequent studies have demonstrated greater flexibility, or plasticity, in effector T cell stability than originally conceived...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28352109/il-1%C3%AE-induced-hif-1%C3%AE-inhibits-the-differentiation-of-human-foxp3-t-cells
#6
Lea M Feldhoff, Cesar M Rueda, Maria E Moreno-Fernandez, Johanna Sauer, Courtney M Jackson, Claire A Chougnet, Jan Rupp
Differentiation of regulatory Treg (Treg) in the periphery is critical to control inflammatory processes. Although polarization of inducible Treg (iTreg) often occurs in an inflammatory environment, the effects exerted by inflammation on human iTreg differentiation have not been extensively studied. We observed that IL-1β significantly reduced the frequency of FOXP3(+) T cells under iTreg-polarizing conditions. Mechanistically, we show that IL-1β activated mTORC1 and downstream upregulated hypoxia inducible factor-1 (HIF-1α) expression...
March 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28290453/suppressive-il-17a-foxp3-and-ex-th17-il-17a-neg-foxp3-treg-cells-are-a-source-of-tumour-associated-treg-cells
#7
Stephanie Downs-Canner, Sara Berkey, Greg M Delgoffe, Robert P Edwards, Tyler Curiel, Kunle Odunsi, David L Bartlett, Nataša Obermajer
Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Treg imbalance is associated with inflammatory immunosuppression in cancer. Here we show that Th17 cells are a source of tumour-induced Foxp3(+) cells. In addition to natural (n)Treg and induced (i)Treg cells that develop from naive precursors, suppressive IL-17A(+)Foxp3(+) and ex-Th17 Foxp3(+) cells are converted from IL-17A(+)Foxp3(neg) cells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A(+), ex-Th17 and iTreg cells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing Treg cell subsets...
March 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28287407/membrane-organizing-protein-moesin-controls-treg-differentiation-and-antitumor-immunity-via-tgf-%C3%AE-signaling
#8
Ephraim A Ansa-Addo, Yongliang Zhang, Yi Yang, George S Hussey, Breege V Howley, Mohammad Salem, Brian Riesenberg, Shaoli Sun, Don C Rockey, Serhan Karvar, Philip H Howe, Bei Liu, Zihai Li
Moesin is a member of the ezrin-radixin-moesin (ERM) family of proteins that are important for organizing membrane domains and receptor signaling and regulating the migration of effector T cells. Whether moesin plays any role during the generation of TGF-β-induced Tregs (iTregs) is unknown. Here, we have discovered that moesin is translationally regulated by TGF-β and is also required for optimal TGF-β signaling that promotes efficient development of iTregs. Loss of moesin impaired the development and function of both peripherally derived iTregs and in vitro-induced Tregs...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28276457/cd40-signalling-abrogates-induction-of-ror%C3%AE-t-treg-cells-by-intestinal-cd103-dcs-and-causes-fatal-colitis
#9
Christian Barthels, Ana Ogrinc, Verena Steyer, Stefanie Meier, Ferdinand Simon, Maria Wimmer, Andreas Blutke, Tobias Straub, Ursula Zimber-Strobl, Esther Lutgens, Peggy Marconi, Caspar Ohnmacht, Debora Garzetti, Bärbel Stecher, Thomas Brocker
Immune homeostasis in intestinal tissues depends on the generation of regulatory T (Treg) cells. CD103(+) dendritic cells (DCs) acquire microbiota-derived material from the gut lumen for transport to draining lymph nodes and generation of receptor-related orphan γt(+) (RORγt(+)) Helios(-)-induced Treg (iTreg) cells. Here we show CD40-signalling as a microbe-independent signal that can induce migration of CD103(+) DCs from the lamina propria (LP) to the mesenteric lymph nodes. Transgenic mice with constitutive CD11c-specific CD40-signalling have reduced numbers of CD103(+) DCs in LP and a low frequency of RORγt(+)Helios(-) iTreg cells, exacerbated inflammatory Th1/Th17 responses, high titres of microbiota-specific immunoglobulins, dysbiosis and fatal colitis, but no pathology is detected in other tissues...
March 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28272545/glycyrrhiza-uralensis-water-extract-enhances-dendritic-cell-maturation-and-antitumor-efficacy-of-hpv-dendritic-cell-based-vaccine
#10
Adila Aipire, Jinyu Li, Pengfei Yuan, Jiang He, Yelang Hu, Lu Liu, Xiaoli Feng, Yijie Li, Fuchun Zhang, Jianhua Yang, Jinyao Li
Licorice has been used as herbal medicine and natural sweetener. Here, we prepared Glycyrrhiza uralensis water extract (GUWE) and investigated the effect of GUWE on the maturation and function of dendritic cells (DCs) and its adjuvant effect on DC-based vaccine. We observed that GUWE dose-dependently promoted DC maturation and cytokine secretion through TLR4 signaling pathway. The capacity of DC to stimulate allogenic splenocyte proliferation was also enhanced by GUWE treatment. Compared with control group, GUWE treated DCs pulsed with human papillomavirus (HPV)-16 E6/E7 peptides significantly inhibited the tumor growth in both early and late therapeutic groups...
March 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28249894/targeting-cd38-suppresses-induction-and-function-of-t-regulatory-cells-to-mitigate-immunosuppression-in-multiple-myeloma
#11
Xiaoyan Feng, Li Zhang, Chirag Acharya, Gang An, Kenneth Wen, Luqui Qiu, Nikhil C Munshi, Yu-Tzu Tai, Kenneth C Anderson
PURPOSE: We study CD38 levels in immunosuppressive CD4+CD25highFoxp3+ Tregs and further define immune modulating effects of a therapeutic CD38 monoclonal antibody (mAb) Isatuximab (Isa)/SAR650984 in multiple myeloma (MM). EXPERIMENTAL DESIGN: We evaluated percentages of CD38-expressing subsets in Tregs from normal donors and MM patients. PBMCs were then treated with Isa with or without Lenalidomide (Len) or Pomalidomide (Pom) to identify their impact on percentage and immunosuppressive activity of Tregs on CD4+CD25- T cells (Tcons)...
March 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28194047/progranulin-inhibits-human-t-lymphocyte-proliferation-by-inducing-the-formation-of-regulatory-t-lymphocytes
#12
Kyu Hwan Kwack, Hyeon-Woo Lee
We have examined the effect of progranulin (PGRN) on human T cell proliferation and its underlying mechanism. We show that PGRN inhibits the PHA-induced multiplication of T lymphocytes. It increases the number of iTregs when T lymphocytes are activated by PHA but does not do so in the absence of PHA. PGRN-mediated inhibition of T lymphocyte proliferation, as well as the induction of iTregs, was completely reversed by a TGF-β inhibitor or a Treg inhibitor. PGRN induced TGF-β secretion in the presence of PHA whereas it did not in the absence of PHA...
2017: Mediators of Inflammation
https://www.readbyqxmd.com/read/28167605/thymus-derived-regulatory-t-cell-development-is-regulated-by-c-type-lectin-mediated-bic-microrna-155-expression
#13
Raquel Sánchez-Díaz, Rafael Blanco-Dominguez, Sandra Lasarte, Katerina Tsilingiri, Enrique Martín-Gayo, Beatriz Linillos-Pradillo, Hortensia de la Fuente, Francisco Sánchez-Madrid, Rinako Nakagawa, María L Toribio, Pilar Martín
Thymus-derived regulatory T (tTreg) cells are key to preventing autoimmune diseases, but the mechanisms involved in their development remain unsolved. Here, we show that the C-type lectin receptor CD69 controls tTreg cell development and peripheral Treg cell homeostasis through the regulation of BIC/microRNA 155 (miR-155) and its target, suppressor of cytokine signaling 1 (SOCS-1). Using Foxp3-mRFP/cd69(+/-) or Foxp3-mRFP/cd69(-/-) reporter mice and short hairpin RNA (shRNA)-mediated silencing and miR-155 transfection approaches, we found that CD69 deficiency impaired the signal transducer and activator of transcription 5 (STAT5) pathway in Foxp3(+) cells...
May 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28164173/tgf-%C3%AE-1-along-with-other-platelet-contents-augments-treg-cells-to-suppress-anti-fviii-immune-responses-in-hemophilia-a-mice
#14
Dipica Haribhai, Xiaofeng Luo, Juan Chen, Shuang Jia, Linzheng Shi, Jocelyn A Schroeder, Hartmut Weiler, Richard H Aster, Martin J Hessner, Jianda Hu, Calvin B Williams, Qizhen Shi
Platelets are a rich source of many cytokines and chemokines including transforming growth factor β 1 (TGF-β1). TGF-β1 is required to convert conventional CD4(+) T (Tconv) cells into induced regulatory T (iTreg) cells that express the transcription factor Foxp3. Whether platelet contents will affect Treg cell properties has not been explored. In this study, we show that unfractionated platelet lysates (pltLys) containing TGF-β1 efficiently induced Foxp3 expression in Tconv cells. The common Treg cell surface phenotype and in vitro suppressive activity of unfractionated pltLys-iTreg cells were similar to those of iTreg cells generated using purified TGF-β1 (purTGFβ-iTreg) cells...
December 13, 2016: Blood Advances
https://www.readbyqxmd.com/read/28160290/regulatory-t-cells-and-type-2-innate-lymphoid-cell-dependent-asthma
#15
REVIEW
J L Aron, O Akbari
Group 2 innate lymphoid cells (ILC2s) are a recently identified group of cells with the potent capability to produce Th2-type cytokines such as interleukin (IL)-5 and IL-13. Several studies suggest that ILC2s play an important role in the development of allergic diseases and asthma. Activation of pulmonary ILC2s in murine models lacking T and B cells induces eosinophilia and airway hyper-reactivity (AHR), which are cardinal features of asthma. More importantly, numerous recent studies have highlighted the role of ILC2s in asthma persistence and exacerbation among human subjects, and thus, regulation of pulmonary ILC2s is a major area of investigation aimed at curbing allergic lung inflammation and exacerbation...
February 4, 2017: Allergy
https://www.readbyqxmd.com/read/28125560/o-012-il-36-signaling-controls-the-induced-regulatory-t-cell-th9-cell-balance-and-gut-inflammation
#16
Akihito Harusato, Hirohito Abo, Vu Ngo, Samuel Yi, Satoru Osuka, Jakob Kohlmeier, Jian-Dong Li, Andrew Gewirtz, Asma Nusrat, Timothy Denning
BACKGROUND: In the United States over 1.4 million people suffer from inflammatory bowel disease (IBD). Therefore, there is a pressing need for the development of novel molecular therapeutics targeting pro-inflammatory mediators. Recently a novel interleukin-1 family member, IL-36γ was shown to be up-regulated in patients with inflammatory bowel disease (IBD) and to play an important role in healing of acute intestinal damage in mice, however, the function of IL-36γ with regards to T helper (TH) cell differentiation during gut inflammation remains undefined...
February 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28114290/the-transcription-factor-musculin-promotes-the-unidirectional-development-of-peripheral-treg-cells-by-suppressing-the-th2-transcriptional-program
#17
Chuan Wu, Zuojia Chen, Valerie Dardalhon, Sheng Xiao, Theresa Thalhamer, Mengyang Liao, Asaf Madi, Rafael F Franca, Timothy Han, Mohammed Oukka, Vijay Kuchroo
Although master transcription factors (TFs) are key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress the development of other, non-specific T cell lineages has not been fully elucidated. Through the use of regulatory T cells (Treg cells) induced by transforming growth factor-β (TGF-β), we identified the TF musculin (MSC) as being critical for the development of induced Treg cells (iTreg cells) by repression of the T helper type 2 (TH2) transcriptional program...
March 2017: Nature Immunology
https://www.readbyqxmd.com/read/28077684/targeting-aurora-kinase-a-and-jak2-prevents-gvhd-while-maintaining-treg-and-antitumor-ctl-function
#18
Brian C Betts, Anandharaman Veerapathran, Joseph Pidala, Hua Yang, Pedro Horna, Kelly Walton, Christopher L Cubitt, Steven Gunawan, Harshani R Lawrence, Nicholas J Lawrence, Said M Sebti, Claudio Anasetti
Graft-versus-host disease (GVHD) is a leading cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation. T cell costimulation by CD28 contributes to GVHD, but prevention is incomplete when targeting CD28, downstream mammalian target of rapamycin (mTOR), or Aurora A. Likewise, interleukin-6 (IL-6)-mediated Janus kinase 2 (JAK2) signaling promotes alloreactivity, yet JAK2 inhibition does not eliminate GVHD. We provide evidence that blocking Aurora A and JAK2 in human T cells is synergistic in vitro, prevents xenogeneic GVHD, and maintains antitumor responses by cytotoxic T lymphocytes (CTLs)...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28060341/in-vitro-differentiation-of-human-cd4-foxp3-induced-regulatory-t-cells-itregs-from-na%C3%A3-ve-cd4-t-cells-using-a-tgf-%C3%AE-containing-protocol
#19
Angelika Schmidt, Szabolcs Éliás, Rubin N Joshi, Jesper Tegnér
Regulatory T cells (Tregs) are an integral part of peripheral tolerance, suppressing immune reactions against self-structures and thus preventing autoimmune diseases. Clinical approaches to adoptively transfer Tregs, or to deplete Tregs in cancer, are underway with promising first outcomes. Because the number of naturally occurring Tregs (nTregs) is very limited, studying certain Treg features using in vitro induced Tregs (iTregs) can be advantageous. To date, the best although not absolutely specific protein marker to delineate Tregs is the transcription factor FOXP3...
December 30, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28059703/glycolysis-and-glutaminolysis-cooperatively-control-t-cell-function-by-limiting-metabolite-supply-to-n-glycosylation
#20
Lindsey Araujo, Phillip Khim, Haik Mkhikian, Christie-Lynn Mortales, Michael Demetriou
Rapidly proliferating cells switch from oxidative phosphorylation to aerobic glycolysis plus glutaminolysis, markedly increasing glucose and glutamine catabolism. Although Otto Warburg first described aerobic glycolysis in cancer cells >90 years ago, the primary purpose of this metabolic switch remains controversial. The hexosamine biosynthetic pathway requires glucose and glutamine for de novo synthesis of UDP-GlcNAc, a sugar-nucleotide that inhibits receptor endocytosis and signaling by promoting N-acetylglucosamine branching of Asn (N)-linked glycans...
January 6, 2017: ELife
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