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Regulatory t cells

Sarita Rani Jaiswal, Prakash Bhakuni, Aby Joy, Nisha Murli, Ashok Rajoreya, Aditi Chakrabarti, Suparno Chakrabarti
To understand the phenomenon of early alloreactivity (EA) in younger children undergoing post-transplantation cyclophosphamide (PTCy) based haploidentical transplantation, we studied the graft composition and the immune reconstitution in 32 consecutive patients (age 2-25 years) undergoing PTCy and T cell costimulation blockade based PBSC transplantation with emphasis on CD45RA+ subset of Tregs. All but one engrafted and 14 patients experienced EA (acuteGVHD grade II-IV- 8 and PTHPS-6) with a cumulative incidence of 43...
June 12, 2018: Biology of Blood and Marrow Transplantation
Qiang Ma, Junning Liu, Guoliang Wu, Mujian Teng, Shaoxuan Wang, Meng Cui, Yuantao Li
Regulatory T (Treg) cells are critical suppressors of inflammation and are thought to exert mainly deleterious effects in cancers. In colorectal cancer (CRC), Foxp3+  Treg accumulation in the tumor was associated with poor prognosis. Hence, we examined the circulating Treg cells in CRC patients. Compared to controls, CRC patients presented mild upregulations in CD4+ CD25+/hi T cells and in the more canonical CD4+ CD25+/hi Foxp3+ Treg cells in peripheral blood mononuclear cells. Both of these Treg populations could be roughly divided into LAG3- TIM3- and LAG3+ TIM3+ subsets...
June 15, 2018: Clinical and Experimental Pharmacology & Physiology
Sangeeta Goswami, Irina Apostolou, Jan Zhang, Jill Skepner, Swetha Anandhan, Xuejun Zhang, Liangwen Xiong, Patrick Trojer, Ana Aparicio, Sumit K Subudhi, James P Allison, Hao Zhao, Padmanee Sharma
EZH2-mediated epigenetic regulation of T cell differentiation and regulatory T cell function has been described previously; however, the role of EZH2 in T cell-mediated anti-tumor immunity, especially in the context of immune checkpoint therapy, is not understood. Here, we showed that genetic depletion of EZH2 in regulatory T cells (FoxP3creEZH2fl/fl mice) leads to robust anti-tumor immunity. In addition, pharmacological inhibition of EZH2 in human T cells using CPI-1205 elicited phenotypic and functional alterations of the regulatory T cells and enhanced cytotoxic activity of effector T cells...
June 15, 2018: Journal of Clinical Investigation
Reetta Vanhanen, Anni Tuulasvaara, Joonatan Mattila, Tommi Pätilä, T Petteri Arstila
Thymic commitment of human FOXP3+ regulatory T cells begins at the double positive (DP) CD4+ CD8+ stage. In the current study we show that interleukin-2 promotes the development of FOXP3+ thymocytes and enhances their survival at the DP phase. IL-2 increases the frequency of FOXP3+ cells and promotes the Treg phenotype after TCR-mediated positive selection at the most mature DP stage. However, it has no effect on FOXP3+ cells at the earlier maturation steps before positive selection. DP FOXP3+ are highly susceptible to cell death but IL-2 promotes their survival...
June 15, 2018: Scandinavian Journal of Immunology
Alex Karlsson-Parra, Juliana Kovacka, Emilia Heimann, Margareth Jorvid, Sijme Zeilemaker, Sharon Longhurst, Peter Suenaert
Intratumoral administration of an immune primer is a therapeutic vaccine strategy aimed to trigger dendritic cell (DC)-mediated cross-presentation of cell-associated tumor antigens to cytotoxic CD8+ T cells without the need for tumor antigen characterization. The prevailing view is that these cross-presenting DCs have to be directly activated by pathogen-associated molecular patterns (PAMPS), including Toll-like receptor ligands or live microbial agents like oncolytic viruses. Emerging data are however challenging this view, indicating that the cross-presenting machinery in DCs is suboptimally activated by direct PAMP recognition, and that endogenous inflammatory factors are the main drivers of DC-mediated cross-presentation within the tumor...
June 14, 2018: Pharmaceutical Research
Nicla Porciello, Martina Kunkl, Loretta Tuosto
Regulation of immune responses is critical for ensuring pathogen clearance and for preventing reaction against self-antigens. Failure or breakdown of immunological tolerance results in autoimmunity. CD28 is an important co-stimulatory receptor expressed on T cells that, upon specific ligand binding, delivers signals essential for full T-cell activation and for the development and homeostasis of suppressive regulatory T cells. Many in vivo mouse models have been used for understanding the role of CD28 in the maintenance of immune homeostasis, thus leading to the development of CD28 signaling modulators that have been approved for the treatment of some autoimmune diseases...
2018: F1000Research
Tong Shao, Wei Shi, Jia-Yu Zheng, Xiao-Xiao Xu, Ai-Fu Lin, Li-Xin Xiang, Jian-Zhong Shao
CD58 and CD2 have long been known as a pair of reciprocal adhesion molecules involved in the immune modulations of CD8+ T and NK-mediated cellular immunity in humans and several other mammals. However, the functional roles of CD58 and CD2 in CD4+ T-mediated adaptive humoral immunity remain poorly defined. Moreover, the current functional observations of CD58 and CD2 were mainly acquired from in vitro assays, and in vivo investigation is greatly limited due to the absence of a Cd58 homology in murine models...
2018: Frontiers in Immunology
Elizabeth F Wallin, Danika L Hill, Michelle A Linterman, Kathryn J Wood
Background: T follicular helper (Tfh) cells are key players in the production of antibody-producing B cells via the germinal center reaction. Therapeutic strategies targeting Tfh cells are important where antibody formation is implicated in disease, such as transplant rejection and autoimmune diseases. We investigated the impact of the immunosuppressive agent tacrolimus on human Tfh cell differentiation and function in transplant recipients. Methods: Paired blood and lymph node (LN) samples were obtained from 61 transplant recipients immediately prior to organ implantation...
2018: Frontiers in Immunology
Georgina Flórez-Grau, Irati Zubizarreta, Raquel Cabezón, Pablo Villoslada, Daniel Benitez-Ribas
The identification of activated T-lymphocytes restricted to myelin-derived immunogenic peptides in multiple sclerosis (MS) and aquaporin-4 water channel in neuromyelitis optica (NMO) in the blood of patients opened the possibility for developing highly selective and disease-specific therapeutic approaches. Antigen presenting cells and in particular dendritic cells (DCs) represent a strategy to inhibit pro-inflammatory T helper cells. DCs are located in peripheral and lymphoid tissues and are essential for homeostasis of T cell-dependent immune responses...
2018: Frontiers in Immunology
Huantian Cui, Yuzi Cai, Li Wang, Beitian Jia, Junchen Li, Shuwu Zhao, Xiaoqian Chu, Jin Lin, Xiaoyu Zhang, Yuhong Bian, Pengwei Zhuang
Berberine (BBR), an alkaloid isolated from Rhizoma Coptidis, Cortex Phellode , and Berberis , has been widely used in the treatment of ulcerative colitis (UC). However, the mechanism of BBR on UC is unknown. In this study, we investigated the activities of T regulatory cell (Treg) and T helper 17 cell (Th17) in a dextran sulfate sodium (DSS)-induced UC mouse model after BBR administration. We also investigated the changes of gut microbiota composition using 16S rRNA analysis. We also examined whether BBR could regulate the Treg/Th17 balance by modifying gut microbiota...
2018: Frontiers in Pharmacology
Antoni Xavier Torres-Collado, Ali R Jazirehi
Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8⁺ T cells (CTL)-resistance in NHL remain elusive...
June 14, 2018: Cancers
Claudio Ponte de Albuquerque, Raymond T Suhandynata, Christopher R Carlson, Wei-Tsuang Yuan, Huilin Zhou
Ulp1 and Ulp2, in the yeast Saccharomyces cerevisiae, are the founding members of deSUMOylating enzymes. These enzymes remove Small Ubiquitin-like Modifier (SUMO) from proteins and are conserved in all eukaryotes. Previous studies have shown that Ulp1 deSUMOylates the bulk of intracellular SUMOylated proteins, while Ulp2 is a highly specific enzyme. However, the mechanism for Ulp2's substrate specificity has been insufficiently understood. Here we show that the C-terminal regulatory domain of Ulp2 contains three distinct, yet conserved, motifs that control its in vivo substrate specificity and cell growth...
June 14, 2018: Journal of Biological Chemistry
Yi Yang, Xiao He, Rongseng Zhao, Wei Guo, Ming Zhu, Wei Xing, Dongpo Jiang, Chongyang Liu, Xiang Xu
BACKGROUND: To explore the mechanism of the different clinical efficacies of mesenchymal stem cell transplantation (MSCT) and identify a possible serum biomarker for predicting the therapeutic effect of MSCT in rheumatoid arthritis (RA) patients. METHODS: A total of 105 patients with persistently active RA and poor responses to traditional medication were randomly divided into MSCT and control groups. Outcomes were evaluated according to the 28-joint Disease Activity Score and Health Assessment Questionnaire, serological indicators, regulatory T cell (Treg) to T helper 17 (Th17) cell ratio, and inflammatory cytokine levels...
June 15, 2018: Journal of Translational Medicine
Aida S Hansen, Josefine Slater, Mette Biltoft, Bettina B Bundgaard, Bjarne K Møller, Per Höllsberg
Similar to CD4+ T cells, precursor CD8+ T cells are thought to depend on a co-stimulatory signal through CD28 for proliferation and differentiation into effector cells. CD46 is another co-stimulatory receptor that promotes differentiation of CD4+ T-helper cells type 1 (Th1 cells) into a regulatory phenotype with a switch from IFN-γ towards IL-10-secretion over time. Whether CD46 exerts a similar function on CD8+ T cells remains to be fully elucidated. Here, we demonstrate that CD46 co-stimulation induced secretion of IFN-γ as well as expansion of IFN-γ-secreting CD8+ T cells...
June 11, 2018: Immunology Letters
Tzu-Sheng Hsu, Ming-Zong Lai
Hypoxia-inducible factor 1α (HIF-1α) regulates cellular responses to hypoxia. However, conflicting roles for HIF-1α in the functions of regulatory T cells (Tregs) have been reported. In this review, we summarize observations on the requirement for HIF-1α for FOXP3 expression and Tregs development, as well as for HIF-1α-mediated downregulation of FOXP3 and Tregs destabilization. We also examine the association of HIF-1α with Tregs under pathogenic conditions. Based on these findings, we suggest that HIF-1α mainly plays a detrimental role in the function and stability of Tregs and that HIF-1α is disposable for the development and suppressive function of Tregs...
June 14, 2018: Journal of Leukocyte Biology
Jessica Mandrioli, Roberto D'Amico, Elisabetta Zucchi, Annalisa Gessani, Nicola Fini, Antonio Fasano, Claudia Caponnetto, Adriano Chiò, Eleonora Dalla Bella, Christian Lunetta, Letizia Mazzini, Kalliopi Marinou, Gianni Sorarù, Sara de Biasi, Domenico Lo Tartaro, Marcello Pinti, Andrea Cossarizza
INTRODUCTION: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions...
June 2018: Medicine (Baltimore)
Ashley Volaric, Ryan Gentzler, Richard Hall, James H Mehaffey, Edward B Stelow, Timothy N Bullock, Linda W Martin, Anne M Mills
The immune regulatory enzyme indoleamine-2,3-dioxygenase (IDO-1) suppresses T cell responses and may reduce efficacy of therapies targeting immune checkpoints such as programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1). Early phase clinical trials combining IDO-1 and PD-1/PD-L1 inhibitors have shown some promise in non-small cell lung cancers (NSCLCs). However, the coexpression of IDO-1 and PD-L1 has not been thoroughly investigated, and the potential for IDO-1 immunohistochemical expression as a therapeutic biomarker is unknown...
June 12, 2018: American Journal of Surgical Pathology
Megumi Maeda, Hidenori Matsuzaki, Shoko Yamamoto, Suni Lee, Naoko Kumagai-Takei, Kei Yoshitome, Yu Min, Nagisa Sada, Yasumitsu Nishimura, Takemi Otsuki
Prompted by the known carcinogenic activity of asbestos, our investigations revealed that asbestos causes a reduction in antitumor immunity. One mechanism involves the enhancement of regulatory T (Treg) cell function and volume assayed using MT‑2 original cells (Org), an HTLV‑1 immortalized human T cell line which possesses Treg‑like function. Continuous and relatively low‑dose exposure of MT‑2 to asbestos fibers yielded sublines resistant to asbestos‑induced apoptosis and enhanced Treg function via cell‑cell contact mechanisms and increased the production of soluble factors such as interleukin (IL)‑10 and transforming growth factor (TGF)‑β...
June 7, 2018: Oncology Reports
Sichao Zhang, Xi Chen, Ichinkhorloo Devshilt, Qi Yun, Cong Huang, Lijun An, Sosorburam Dorjbat, Xin He
Fennel, commonly used in traditional Chinese medicine, is known as Foeniculum vulgare Mill. And its clinical application has been shown to target many biological systems including gastroenterology, endocrinology, gynecology and respiratory. The main constituent of the fennel essential oil is trans‑anethole, which has been described to have anti‑inflammatory and antibacterial activities. The aim of the present study was to define the anti‑inflammatory influence in acute lung injury (ALI)‑bearing mice...
June 7, 2018: Molecular Medicine Reports
Guoying Zhou, Lisanne Noordam, Dave Sprengers, Michail Doukas, Patrick P C Boor, Adriaan A van Beek, Remco Erkens, Shanta Mancham, Dirk Grünhagen, Anand G Menon, Johan F Lange, Pim J W A Burger, Alexandra Brandt, Boris Galjart, Cornelis Verhoef, Jaap Kwekkeboom, Marco J Bruno
Purpose : Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology : Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC...
2018: Oncoimmunology
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