scholarly journals Tr1 Cells as a Key Regulator for Maintaining Immune Homeostasis in Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yun Song ◽  
Ning Wang ◽  
Lihua Chen ◽  
Liang Fang
Keyword(s):  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Immune Homeostasis ◽  
Forkhead Box P3 ◽  
Forkhead Box ◽  
Distinct Subset ◽  
Regulatory Capacity ◽  
Tr1 Cells

The immune system is composed of effectors and regulators. Type 1 regulatory T (Tr1) cells are classified as a distinct subset of T cells, and they secret high levels of IL-10 but lack the expression of the forkhead box P3 (Foxp3). Tr1 cells act as key regulators in the immune network, and play a central role in maintaining immune homeostasis. The regulatory capacity of Tr1 cells depends on many mechanisms, including secretion of suppressive cytokines, cell-cell contacts, cytotoxicity and metabolic regulation. A breakdown of Tr1-cell-mediated tolerance is closely linked with the pathogenesis of various diseases. Based on this observation, Tr1-cell therapy has emerged as a successful treatment option for a number of human diseases. In this review, we describe an overview of Tr1 cell identification, functions and related molecular mechanisms. We also discuss the current protocols to induce/expand Tr1 cells in vitro for clinical application, and summarize the recent progress of Tr1 cells in transplantation.

scholarly journals Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10–dependent ILT4/HLA-G pathway

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 935-944 ◽  
Author(s):  
Silvia Gregori ◽  
Daniela Tomasoni ◽  
Valentina Pacciani ◽  
Miriam Scirpoli ◽  
Manuela Battaglia ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Interleukin 10 ◽  
Regulatory Cells ◽  
Hla Dr ◽  
Human Dendritic Cells ◽  
Tr1 Cells

Abstract Type 1 T regulatory (Tr1) cells suppress immune responses in vivo and in vitro and play a key role in maintaining tolerance to self- and non–self-antigens. Interleukin-10 (IL-10) is the crucial driving factor for Tr1 cell differentiation, but the molecular mechanisms underlying this induction remain unknown. We identified and characterized a subset of IL-10–producing human dendritic cells (DCs), termed DC-10, which are present in vivo and can be induced in vitro in the presence of IL-10. DC-10 are CD14+, CD16+, CD11c+, CD11b+, HLA-DR+, CD83+, CD1a−, CD1c−, express the Ig-like transcripts (ILTs) ILT2, ILT3, ILT4, and HLA-G antigen, display high levels of CD40 and CD86, and up-regulate CD80 after differentiation in vitro. DC-10 isolated from peripheral blood or generated in vitro are potent inducers of antigen-specific IL-10–producing Tr1 cells. Induction of Tr1 cells by DC-10 is IL-10–dependent and requires the ILT4/HLA-G signaling pathway. Our data indicate that DC-10 represents a novel subset of tolerogenic DCs, which secrete high levels of IL-10, express ILT4 and HLA-G, and have the specific function to induce Tr1 cells.

scholarly journals BHLHE40 Regulates IL-10 and IFN-γ Production in T Cells but Does Not Interfere With Human Type 1 Regulatory T Cell Differentiation

2021 ◽  
Vol 12 ◽  
Author(s):  
Molly Javier Uyeda ◽  
Robert A. Freeborn ◽  
Brandon Cieniewicz ◽  
Rosa Romano ◽  
Ping (Pauline) Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Ex Vivo ◽  
Surface Expression ◽  
Surface Molecules ◽  
Ifn Γ ◽  
And Function ◽  
Tr1 Cells

Type 1 regulatory T (Tr1) cells are subset of peripherally induced antigen-specific regulatory T cells. IL-10 signaling has been shown to be indispensable for polarization and function of Tr1 cells. However, the transcriptional machinery underlying human Tr1 cell differentiation and function is not yet elucidated. To this end, we performed RNA sequencing on ex vivo human CD49b+LAG3+ Tr1 cells. We identified the transcription factor, BHLHE40, to be highly expressed in Tr1 cells. Even though Tr1 cells characteristically produce high levels of IL-10, we found that BHLHE40 represses IL-10 and increases IFN-γ secretion in naïve CD4+ T cells. Through CRISPR/Cas9-mediated knockout, we determined that IL10 significantly increased in the sgBHLHE40-edited cells and BHLHE40 is dispensable for naïve CD4+ T cells to differentiate into Tr1 cells in vitro. Interestingly, BHLHE40 overexpression induces the surface expression of CD49b and LAG3, co-expressed surface molecules attributed to Tr1 cells, but promotes IFN-γ production. Our findings uncover a novel mechanism whereby BHLHE40 acts as a regulator of IL-10 and IFN-γ in human CD4+ T cells.

scholarly journals Glycosylation of CaV3.2 Channels Contributes to the Hyperalgesia in Peripheral Neuropathy of Type 1 Diabetes

2020 ◽  
Vol 14 ◽  
Author(s):  
Sonja Lj. Joksimovic ◽  
J. Grayson Evans ◽  
William E. McIntire ◽  
Peihan Orestes ◽  
Paula Q. Barrett ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Adult Female ◽  
Molecular Mechanisms ◽  
Sprague Dawley ◽  
Knock Out ◽  
Peripheral Diabetic Neuropathy ◽  
Novel Treatments

Our previous studies implicated glycosylation of the CaV3.2 isoform of T-type Ca2+ channels (T-channels) in the development of Type 2 painful peripheral diabetic neuropathy (PDN). Here we investigated biophysical mechanisms underlying the modulation of recombinant CaV3.2 channel by de-glycosylation enzymes such as neuraminidase (NEU) and PNGase-F (PNG), as well as their behavioral and biochemical effects in painful PDN Type 1. In our in vitro study we used whole-cell recordings of current-voltage relationships to confirm that CaV3.2 current densities were decreased ~2-fold after de-glycosylation. Furthermore, de-glycosylation induced a significant depolarizing shift in the steady-state relationships for activation and inactivation while producing little effects on the kinetics of current deactivation and recovery from inactivation. PDN was induced in vivo by injections of streptozotocin (STZ) in adult female C57Bl/6j wild type (WT) mice, adult female Sprague Dawley rats and CaV3.2 knock-out (KO mice). Either NEU or vehicle (saline) were locally injected into the right hind paws or intrathecally. We found that injections of NEU, but not vehicle, completely reversed thermal and mechanical hyperalgesia in diabetic WT rats and mice. In contrast, NEU did not alter baseline thermal and mechanical sensitivity in the CaV3.2 KO mice which also failed to develop painful PDN. Finally, we used biochemical methods with gel-shift analysis to directly demonstrate that N-terminal fragments of native CaV3.2 channels in the dorsal root ganglia (DRG) are glycosylated in both healthy and diabetic animals. Our results demonstrate that in sensory neurons glycosylation-induced alterations in CaV3.2 channels in vivo directly enhance diabetic hyperalgesia, and that glycosylation inhibitors can be used to ameliorate painful symptoms in Type 1 diabetes. We expect that our studies may lead to a better understanding of the molecular mechanisms underlying painful PDN in an effort to facilitate the discovery of novel treatments for this intractable disease.

Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1

2019 ◽  
Vol 11 (488) ◽  
pp. eaau7116 ◽  
Author(s):  
Shiming Peng ◽  
Wen Xiao ◽  
Dapeng Ju ◽  
Baofa Sun ◽  
Nannan Hou ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Metabolic Disorders ◽  
Fasting Blood Glucose ◽  
Reduced Body ◽  
Forkhead Box ◽  
Obesity And Diabetes ◽  
Approved Drugs ◽  
Blood Glucose Concentrations ◽  
Precise Molecular Mechanism

Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Administration–approved drugs to identify entacapone as a potential FTO inhibitor. Using structural and biochemical studies, we showed that entacapone directly bound to FTO and inhibited FTO activity in vitro. Furthermore, entacapone administration reduced body weight and lowered fasting blood glucose concentrations in diet-induced obese mice. We identified the transcription factor forkhead box protein O1 (FOXO1) mRNA as a direct substrate of FTO, and demonstrated that entacapone elicited its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis.

scholarly journals Parainfluenza Virus Type 1 Induces Epithelial IL-8 Production via p38-MAPK Signalling

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Miguel Ángel Galván Morales ◽  
Carlos Cabello Gutiérrez ◽  
Fidencio Mejía Nepomuceno ◽  
Leticia Valle Peralta ◽  
Elba Valencia Maqueda ◽  
...  
Keyword(s):  
Viral Replication ◽  
Cell Lines ◽  
Virus Type ◽  
Molecular Mechanisms ◽  
Parainfluenza Virus ◽  
Kinase Activation ◽  
Mitogen Activated Protein ◽  
Human Parainfluenza Virus

Human parainfluenza virus type 1 (HPIV-1) is the most common cause of croup in infants. The aim of this study was to describe molecular mechanisms associated with IL-8 production during HPIV-1 infection and the role of viral replication in MAPK synthesis and activation. Anin vitromodel of HPIV-1 infection in the HEp-2 and A549 cell lines was used; a kinetic-based ELISA for IL-8 detection was also used, phosphorylation of the mitogen-activated protein kinases (MAPKs) was identified by Western blot analysis, and specific inhibitors for each kinase were used to identify which MAPK was involved. Inactivated viruses were used to assess whether viral replication is required for IL-8 production. Results revealed a gradual increase in IL-8 production at different selected times, when phosphorylation of MAPK was detected. The secretion of IL-8 in the two cell lines infected with the HPIV-1 is related to the phosphorylation of the MAPK as well as viral replication. Inhibition of p38 suppressed the secretion of IL-8 in the HEp-2 cells. No kinase activation was observed when viruses were inactivated.

scholarly journals Membrane type 1 matrix metalloproteinase proteolytic activity in initial adhesive and invasive events of ovarian cancer metastasis

2014 ◽  
Author(s):  
◽  
Lana Bruney
Keyword(s):  
Ovarian Cancer ◽  
Extracellular Matrix ◽  
Proteolytic Activity ◽  
Ovarian Tumor ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Ectodomain Shedding ◽  
Metastatic Process

Epithelial ovarian cancer (EOC) is one of the most common gynecologic malignancies, generally developing in women over the age of forty. When EOC are diagnosed prior to metastatic dissemination, the overall 5-year survival rate is 92%; however, nearly 85% of women with EOC are diagnosed with metastasis already present, dropping the survival rate to less than 30%. EOC, arises, arguably, from the single layer of cells that cover the ovary or fallopian tube. Metastatic ovarian tumors develop once an epithelial cell transforms, inducing detachment from the primary tumor site. These shed cells travel throughout the peritoneal cavity, escaping anoikis to survive as single cells and multicellular aggregates (MCA), and metastasize intraperitoneally through adhesion to and invasion of the mesothelial cell layer covering the peritoneum, the primary microenvironment for ovarian cancer metastasis. These mesothelial cells lie atop a collagen type I-rich extracellular matrix; subsequent to the initial attachment of ovarian cancer cells, proteolytic activity catalyzes migration through the mesothelial monolayer and promotes invasion of the sub-mesothelial matrix. Elucidating the early molecular mechanisms involved in this metastatic process, specifically the adhesion of EOC cells to mesothelial cells and penetration of the associated sub-mesothelial extracellular matrix, is essential to the development of future therapeutic agents. Enzymatic activity of matrix type 1 metalloproteinase (MT1-MMP), a transmembrane proteinase that degrades interstitial collagen, has been shown to be critical to this process. MT1-MMP activity has been directly implicated in both the invasion of the sub-mesothelial collagen I matrix, and in the shedding of metastatic MCA, but the molecular mechanisms behind these events are not completely understood. Considering the well-established role of MT1-MMP in the EOC metastatic process, identification of the molecules contributing to these pro-metastatic phenotypes is critical to future understanding of EOC metastatic spread. This research investigated the initial adhesive and invasive events of ovarian cancer metastasis, as associated with MT1-MMP proteolytic activity. Specifically, the effect of MT1-MMP activity on ovarian tumor cell ectodomain shedding and the in vitro, relationship between MT1-MMP and a potential phosphorylator, integrin linked kinase (ILK), on adhesion and invasion was assessed. Investigations utilized in vitro models of homotypic and heterotypic cell-cell adhesion, meso-mimetic invasion assays, and ex vivo tissue explants. Results suggest that ILK activity may catalyze phosphorylation of MT1-MMP to promote pro-metastatic events, including strengthening of adhesive contacts, invasion of the collagen-rich sub-mesothelial matrix, and MCA formation. Additionally, MT1-MMP expression may induce MUC16/CA-125 ectodomain shedding, which may then expose integrins at the ovarian tumor cell surface for high affinity cell-cell and cell-ECM binding.

scholarly journals CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25− T cells

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2537-2544 ◽  
Author(s):  
Zhi-Zhang Yang ◽  
Anne J. Novak ◽  
Steven C. Ziesmer ◽  
Thomas E. Witzig ◽  
Stephen M. Ansell
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Foxp3 Expression ◽  
Regulatory Function ◽  
Forkhead Box P3 ◽  
Non Hodgkin Lymphoma ◽  
Forkhead Box

Foxp3 expression was initially thought to be restricted to the CD4+CD25+ regulatory T-cell population. However, recent studies suggest that forkhead box P3 (Foxp3) is expressed in CD4+CD25− T cells in aged mice. In the present study in B-cell non-Hodgkin lymphoma (NHL), we found that a subset of intratumoral but not peripheral blood CD4+CD25− T cells, comprising about 15% of intratumoral CD4+ T cells, express Foxp3 and are capable of suppressing the proliferation of autologous infiltrating CD8+ T cells. In vitro activation with OKT3/anti-CD28 antibody (Ab) or dendritic cells (DCs) induced Foxp3 expression in a subset of these CD4+CD25−Foxp3− T cells. We found that the presence of lymphoma B cells during activation augmented activation-induced Foxp3 expression in CD4+CD25− T cells. We also found that CD70+ lymphoma B cells significantly contributed to the activation-induced Foxp3 expression in intratumoral CD4+CD25− T cells. Furthermore, the blockade of CD27-CD70 interaction by anti-CD70 Ab abrogated lymphoma B-cell–mediated induction of Foxp3 expression in intratumoral CD4+CD25− T cells. Taken together, these studies reveal a novel role for NHL B cells in the development of intratumoral regulatory T cells.

scholarly journals Differential impacts of TNFα inhibitors on the transcriptome of Th cells

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Ching-Huang Ho ◽  
Andrea A. Silva ◽  
Beverly Tomita ◽  
Hui-Ying Weng ◽  
I-Cheng Ho
Keyword(s):  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Physical Interaction ◽  
Peripheral Blood Mononuclear ◽  
Th Cells ◽  
Specific Effects ◽  
Tnfα Inhibitors

Abstract Background Targeting TNFα is beneficial in many autoimmune and inflammatory diseases, including rheumatoid arthritis. However, the response to each of the existing TNFα inhibitors (TNFis) can be patient- and/or disease-dependent. In addition, TNFis can induce the production of type 1 interferons (IFNs), which contribute to their non-infection side effects, such as pustular psoriasis. Thus far, the molecular mechanisms mediating the drug-specific effects of TNFis and their induction of type 1 IFNs are not fully understood. Methods Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors and stimulated in vitro with anti-CD3 and anti-CD28 in the absence or presence of adalimumab, etanercept, or certolizumab. Th cells were isolated from the stimulated PBMCs, and their RNA was subjected to RNA-seq and quantitative polymerase chain reaction. Results Adalimumab and etanercept, which contain Fc, but not certolizumab, which does not contain Fc, inhibited the expression of several effector cytokines by Th cells within anti-CD3/anti-CD28-stimulated PBMCs. Transcriptomic analyses further showed that adalimumab, but not certolizumab, reciprocally induced type 1 IFN signals and the expression of CD96 and SIRPG in Th cells. The unique effects of adalimumab were not due to preferential neutralization of soluble TNFα but instead were mediated by several distinct mechanisms independent or dependent of Fc-facilitated physical interaction between Th cells and CD14+ monocytes. Conclusions TNFis can have drug-specific effects on the transcriptional profile of Th cells.

scholarly journals Involvement of miR-214-3p/FOXM1 axis during the progression of psoriasis

2021 ◽  
Author(s):  
Jin Zhao ◽  
Fei Wang ◽  
Qingjun Tian ◽  
Jing Dong ◽  
Liuqing Chen ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cyclin B1 ◽  
Mrna Degradation ◽  
Hacat Cells ◽  
Forkhead Box ◽  
Forkhead Box M1 ◽  
Non Coding Rnas ◽  
Novel Target

Abstract Psoriasis is a common, chronic, and relapsing skin disease characterized by hyperproliferation of keratinocytes and apoptosis delay. However, the molecular mechanisms underlying the progression of psoriasis remain elusive. MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs that play a crucial role in the development of psoriasis by promoting targeted mRNA degradation or translational inhibition. Here, we report that miR-214-3p, one of the down-regulated miRNAs identified in the skin of psoriatic patients and imiquimod (IMQ)-induced mouse models, can negatively regulate the expression of forkhead box M1 (FOXM1). miR-214-3p inhibition leads to hyperproliferation and increased apoptosis of keratinocytes in vitro. Moreover, we show that miR-214-3p inhibition causes an arrest of the cell cycle at the S stage by elevating the expression of NEK2, KIF20A, CENP-A, CENP-F, Cyclin B1, and by reducing the expression of Cyclin D1 in HaCaT cells. In vivo, administration of miR-214-3p attenuates the psoriasis-like phenotype in IMQ-induced mice. Collectively, our results suggest that miR-214-3p/FOXM1 axis in keratinocytes could be a novel target in the treatment of psoriasis.

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