scholarly journals Probiotics Improve Autoimmune Hepatitis via Gut Mycobiota-Mediated Follicular Helper T Cells

2021 ◽  
Author(s):  
Liang Ma ◽  
Liwen Zhang ◽  
Yun Zhuang ◽  
Yanbo Ding ◽  
Jianping Chen
Keyword(s):  
T Cells ◽  
Autoimmune Hepatitis ◽  
Therapeutic Potential ◽  
Underlying Mechanism ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Real Time Quantitative Pcr ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Immune Mediated

Abstract Background: Autoimmune hepatitis (AIH) is a chronic, immune-mediated liver dysfunction. The follicular helper (TFH) T cells play critical roles in the immunopathogenesis and progression of AIH. But the underlying mechanism of the dysregulation of TFH cells in AIH remains to be determined. Therefore, we aimed to investigate the effect of gut mycobiota on TFH cell response in AIH. Methods: Samples from AIH patients and the EAH animal model were analyzed using Real-time quantitative PCR (RT-qPCR), Enzyme-linked immunosorbent assay (ELISA), western blotting, flow cytometry, and Hematoxylin-eosin (HE) staining to determine the role of gut mycobiota on autoimmune hepatitis.Results: Lactobacillus capsule could significantly increased the levels of Bacteroides fragilis, Clostridium, Clostridium leptum, Bifi, and Lacto in AIH patients and significantly decreased the levels of ALT, AST, TBIL, SMA, ANA, DAO, and ET in AIH patients. What’s more, the Lactobacillus capsule showed similar results in EAH mice. it decreased the levels of serum IL-21, the proportions of TFH cells in CD4+ T cells as well as TFH related cytokines and factors. Mechanistically, lactobacillus capsule regulated TFH response in EAH mice in DCs and MyD88/NF-κB pathway-dependent manner. Conclusion: Our results suggested a protective and therapeutic potential of probiotics in the treatment of AIH.

scholarly journals Constitutive Changes in Circulating Follicular Helper T Cells and Their Subsets in Patients with Graves’ Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yan Liu ◽  
Xinwang Yuan ◽  
Xiaofang Li ◽  
Dawei Cui ◽  
Jue Xie
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Mrna Expression ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Enzyme Linked Immunosorbent Assay ◽  
Graves Disease ◽  
Mrna Levels ◽  
Tfh Cells ◽  
Follicular Helper

Background. Follicular helper T (Tfh) cells are critical for high-affinity antibody generation and B cell maturation and differentiation, which play important roles in autoimmune diseases. Graves’ disease (GD) is one prototype of common organ-specific autoimmune thyroid diseases (AITD) characterized by autoreactive antibodies, suggesting a possible role for Tfh cells in the pathogenesis of GD. Our objective was to explore the role of circulating Tfh cell subsets and associated plasma cells (PCs) in patients with GD. Methods. Thirty-six patients with GD and 20 healthy controls (HC) were enrolled in this study. The frequencies of circulating Tfh cell subsets and PCs were determined by flow cytometry, and plasma cytokines, including interleukin- (IL-) 21, IL-4, IL-17A, and interferon- (IFN-) γ, were measured using an enzyme-linked immunosorbent assay (ELISA). The mRNA expression of transcription factors (Bcl-6, T-bet, GATA-3, and RORγt) in peripheral blood mononuclear cells (PBMCs) was evaluated by real-time quantitative PCR. Results. Compared with HC, the frequencies of circulating CD4+CXCR5+CD45RA−Tfh (cTfh) cells with ICOS and PD-1 expression, the Tfh2 subset (CXCR3−CCR6−Tfh) cells, and PCs (CD19+CD27highCD38high) were significantly increased in the GD patients, but the frequencies of Tfh1 (CXCR3+CCR6−Tfh) and Tfh17 (CXCR3−CCR6+Tfh) subset cells among CD4+T cells were significantly decreased in GD patients. The plasma concentrations of IL-21, IL-4, and IL-17A were elevated in GD patients. Additionally, a positive correlation was found between the frequency of PD-1+Tfh cells (Tfh2 or PCs) and plasma IL-21 concentration (or serum TPO-Ab levels). The mRNA levels of transcription factors (GATA-3 and RORγt) were significantly increased, but T-bet and Bcl-6 mRNA expression was not obviously varied in PBMCs from GD patients. Interestingly, Tfh cell subsets and PCs from GD patients were partly normalized by treatment. Conclusion. Circulating Tfh cell subsets and PCs might play an important role in the pathogenesis of GD, which are potential clues for GD patients’ interventions.

scholarly journals The Tumor Microenvironment in Follicular Lymphoma: Its Pro-Malignancy Role with Therapeutic Potential

2021 ◽  
Vol 22 (10) ◽  
pp. 5352
Author(s):  
Takashi Watanabe
Keyword(s):  
T Cells ◽  
B Cells ◽  
Follicular Lymphoma ◽  
Therapeutic Potential ◽  
Cytotoxic T Cells ◽  
Interleukin 4 ◽  
Cell Frequency ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Reticular Cells

In the follicular lymphoma (FL) microenvironment, CXCR5+ICOS+PD1+BCL6+ follicular helper T (Tfh) cells, which closely correlate with FL B cells in neoplastic follicles, play a major role in supporting FL. Interleukin-4 secreted by Tfh cells triggers the upregulation of the lymphocyte chemoattractant CXCL12 in stromal cell precursors, in particular by fibroblastic reticular cells (FRCs). In turn, mesenchymal fistromal cells (MSCs) can be committed to FRC differentiation in the bone marrow and lymph nodes involved by FL. Noteworthy, MSCs can promote the differentiation of Tfh cells into highly immunosuppressive T-follicular regulatory cells. The tumor suppressor HVEM is highly mutated in FL cells, and its deficiency increases Tfh cell frequency. In contrast, PI3Kδ inhibition impedes the recruitment of Tfh/regulatory T cells and impairs the proliferation of follicular dendritic cells (FDCs) and FDC-induced angiogenesis. Since TIGIT ligands are expressed by FDCs, the immune checkpoint receptor TIGIT plays an important role in tumor-infiltrating T cells. Thus, TIGIT blockade might invigorate cytotoxic T cells in the FL microenvironment. Given their potential to simultaneously reduce the neoplastic B cells, Tfh, and TFR cells could also reinforce the effects of the cytotoxic T cells. This combinatory strategy should be explored as a treatment option to tackle FL.

scholarly journals IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells

2010 ◽  
Vol 207 (13) ◽  
pp. 2895-2906 ◽  
Author(s):  
Marcel Batten ◽  
Nandhini Ramamoorthi ◽  
Noelyn M. Kljavin ◽  
Cindy S. Ma ◽  
Jennifer H. Cox ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Germinal Center ◽  
Dependent Manner ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Cell Clones

Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (TFH) cells. TFH cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of TFH cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of TFH cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4+ T cells and the expression of TFH cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and TFH cell survival in a T cell–intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra−/− mice. Together, our data show a nonredundant role for IL-27 in the development of T cell–dependent antibody responses.

scholarly journals Human Articular Chondrocytes Induce Interleukin-2 Nonresponsiveness to Allogeneic Lymphocytes

Cartilage ◽  
2016 ◽  
Vol 8 (3) ◽  
pp. 300-306 ◽  
Author(s):  
Satomi Abe ◽  
Hitoshi Nochi ◽  
Hiroshi Ito
Keyword(s):  
T Cells ◽  
Articular Chondrocytes ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Third Party ◽  
Soluble Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Activated T Cells ◽  
Allogeneic Lymphocytes

Introduction We previously showed that articular chondrocytes (ACs) have immune privilege and immunomodulatory functions like those of mesenchymal stem cells. To elucidate these mechanisms, we focused on interleukin-2 (IL-2), which plays critical roles in lymphocyte mitogenic activity. The purpose of this study was to explore whether ACs affect the role of IL-2 underlying immunomodulatory functions. Material and Methods Irradiated human ACs from osteoarthritis donors were used. Third-party ACs were added to the mixed lymphocyte reaction (MLR) with or without recombinant human IL-2 (rhIL-2), and the levels of IL-2 and the soluble form of the IL-2 receptor α (sIL-2Rα) protein in supernatant were measured by enzyme-linked immunosorbent assay. Recombinant human IL-2 (rhIL-2) was also added to the MLR. To detect the expression of IL-2 receptor α (CD25) on lymphocytes in the MLR, flow cytometric analysis was performed. Last, ACs and allogeneic activated CD4+ T cell were co-cultured, and the expression of CD25 on activated T cells was examined by flow cytometry. Results Third-party ACs significantly inhibited the MLR and reduced the level of sIL-2Rα in a dose-dependent manner, but did not affect the concentration of IL-2. Exogenous rhIL-2 accelerated MLR but did not rescue the inhibitory effect of ACs. ACs inhibited the expression of CD25 on activated CD4+ T cells. Discussion Our results showed that third-party ACs inhibited the proliferation of allogeneic activated lymphocytes, thereby inhibiting production sIL-2Rα, although ACs did not affect IL-2 secretion from lymphocytes. Also, ACs inhibited CD25 expression on activated CD4+ T cells. Thus, ACs inhibited the immune response of allogeneic lymphocytes by inducing IL-2 nonresponsiveness.

scholarly journals Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes

2021 ◽  
Author(s):  
Andrea Vecchione ◽  
Tatiana Jofra ◽  
Jolanda Gerosa ◽  
Kimberly Shankwitz ◽  
Roberta Di Fonte ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Organ Donor ◽  
Peripheral Tolerance ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Pancreatic Lymph Nodes ◽  
Cell Alterations ◽  
Humoral Tolerance

In the attempt to understand the origin of autoantibody (AAb) production in patients with and at-risk for T1D, multiple studies have analyzed and reported alterations in follicular helper T cells (Tfh) in presymptomatic AAb-positive subjects and patients with T1D. Yet, it is still not clear whether the regulatory counterpart of Tfh cells, represented by follicular regulatory T cells (Tfr), is similarly altered. To address this question, we performed analyses in peripheral blood, spleen and pancreatic lymph nodes (PLN) of organ donor subjects with T1D. Blood analyses were also performed in living AAb-negative and -positive subjects. While negligible differences in the frequency and phenotype of blood Tfr cells were observed between T1D, AAb-negative and AAb-positive adult subjects, the frequency of Tfr cells was significantly reduced in spleen and PLN of T1D as compared to non-diabetic controls. Furthermore, adoptive transfer of Tfr cells delayed disease development in a mouse model of T1D, a finding that could indicate that Tfr cells play an important role in peripheral tolerance and regulation of autoreactive Tfh cells. Together, our findings provide evidence of Tfr cell alterations within disease-relevant tissues in patients with T1D suggesting a role for Tfr cells in defective humoral tolerance and disease pathogenesis.

Reduced expression of hematopoietic progenitor kinase 1 in T follicular helper cells causes autoimmunity of systemic lupus erythematosus

Lupus ◽  
2021 ◽  
pp. 096120332110625
Author(s):  
Huilin Zhang ◽  
Yuming Xie ◽  
Junke Huang ◽  
Danhong Luo ◽  
Qing Zhang
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cells ◽  
Lupus Erythematosus ◽  
Damage Index ◽  
Enzyme Linked Immunosorbent Assay ◽  
Systemic Lupus ◽  
Hematopoietic Progenitor ◽  
Protein Levels ◽  
Tfh Cells ◽  
Follicular Helper

Backgroud T follicular helper (Tfh) cells have been discovered to be the main CD4+ T cells assisting B cells to produce antibody. They are over activated in patients with systemic lupus erythematosus (SLE) and consequently lead to excessive immunity. Hematopoietic progenitor kinase 1 (HPK1) negatively regulates T cell-mediated immune responses and TCR signal. This study aimed to investigate the roles of HPK1 in SLE Tfh cells. Methods HPK1 mRNA and protein levels in Tfh cells were measured by real-time quantitative PCR and western blot analysis, respectively. The production of IL-21, B cell−activating factor (BAFF), interferon γ (IFNγ), IL-17A, IgM, IgG1, IgG2, and IgG3 were analyzed using enzyme linked immunosorbent assay. Tfh cells proliferation was evaluated with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results HPK1 mRNA and protein levels were significantly reduced in SLE Tfh cells, and negatively correlated with SLE disease activity index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for SLE (SDI). Knocking down HPK1 with siRNA in normal Tfh cells greatly elevated Tfh cells proliferation and secretions of IL-21, BAFF, IFNγ, IgG1, IgG2, and IgG3. There were no marked alterations in IL-17A and IgM productions. The opposite effects were observed in SLE Tfh cells transfected with HPK1 overexpressing plasmid: Tfh cells proliferation and productions of IL-21, BAFF, IFNγ, IgG1, IgG2, and IgG3 were all alleviated. And there were no significant changes in IL-17A and IgM levels. Conclusion Our results suggest for the first time that inhibited expression of HPK1 in SLE Tfh cells leading to Tfh cells overactivation and B cells overstimulation, subsequently, the onset and progression of SLE.

scholarly journals Hsp60 and IL-8 axis promotes apoptosis resistance in cancer

2019 ◽  
Vol 121 (11) ◽  
pp. 934-943 ◽  
Author(s):  
Sandeep Kumar ◽  
Jordan O’Malley ◽  
Ajay Kumar Chaudhary ◽  
Joseph R. Inigo ◽  
Neelu Yadav ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Combined Treatment ◽  
Annexin V ◽  
Underlying Mechanism ◽  
Competitive Inhibitor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Heat Shock Protein 60 ◽  
Apoptosis Resistance ◽  
Upstream Regulator

Abstract Background Interleukin-8 (IL-8) and heat shock protein 60 (Hsp60) play crucial roles in cell survival and maintenance of cellular homoeostasis. However, cross talks between these two proteins are not defined. Methods IL-8 expression in tumour tissue sections was analysed by immunohistochemistry. IL-8 expression and release in cancer cells was quantified using enzyme-linked immunosorbent assay (ELISA). Apoptosis was quantified using caspase activity and Annexin-V/PI staining. Results We observed IL-8 release from cancer cells in response to histone deacetylase inhibitor, apicidin (Api), and non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase, thapsigargin (TG). IL-8 release was increased upon TG-treatment. TG-induced IL-8 expression was reduced in the presence of Api in Bax-dependent manner. Increased apoptosis was associated with decreased IL-8 expression in response to combined treatment of TG and Api. TG and Api combination induced caspase-8 and caspase-9 dependent apoptosis. Hsp60 knockdown abrogated IL-8 expression induced by Api, TG, and their combination. The level of TGF-β, an upstream regulator of IL-8, was decreased upon Hsp60-silencing. Knocking down Hsp60 decreased IL-8 expression and its release in prostate cancer cell xenograft tumours in SCID mice. Conclusion This study describes the underlying mechanism associated with apoptosis resistance mediated via Hsp60-IL-8 axis in cancer.

Bone marrow-derived mesenchymal stem cells inhibit T follicular helper cell in lupus-prone mice

Lupus ◽  
2017 ◽  
Vol 27 (1) ◽  
pp. 49-59 ◽  
Author(s):  
X Yang ◽  
J Yang ◽  
X Li ◽  
W Ma ◽  
H Zou
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
Lupus Nephritis ◽  
Bone Marrow Cells ◽  
Tfh Cells ◽  
Follicular Helper

Background The objective of this paper is to analyze the role of bone marrow-derived mesenchymal stem cells (BM-MSCs) on the differentiation of T follicular helper (Tfh) cells in lupus-prone mice. Methods Bone marrow cells were isolated from C57BL/6 (B6) mice and cultured in vitro, and surface markers were identified by flow cytometry. Naïve CD4+ T cells, splenocytes and Tfh cells were isolated from B6 mice spleens and co-cultured with BM-MSCs. The proliferation and the differentiation of CD4+ T cells and Tfh cells were analyzed by flow cytometry. Lupus-prone MRL/Mp-lpr/lpr (MRL/lpr) mice were treated via intravenous injection with expanded BM-MSCs, the differentiation of Tfh cells was detected, and the relief of lupus nephritis was analyzed. Results MSCs could be successfully induced from bone marrow cells, and cultured BM-MSCs could inhibit T cell proliferation dose-dependently. BM-MSCs could prevent Tfh cell development from naïve CD4+ T cells and splenocytes. BM-MSCs could inhibit IL-21 gene expression and cytokine production and inhibit isolated Tfh cells and STAT3 phosphorylation. In vivo study proved that BM-MSCs intravenous injection could effectively inhibit Tfh cell expansion and IL-21 production, alleviate lupus nephritis, and prolong the survival rate of lupus-prone mice. Conclusions BM-MSCs could effectively inhibit the differentiation of Tfh cells both in vitro and in vivo. BM-MSC treatment could relieve lupus nephritis, which indicates that BM-MSCs might be a promising therapeutic method for the treatment of SLE.

scholarly journals Inhibition of two-pore channels in antigen-presenting cells promotes the expansion of TNFR2-expressing CD4+Foxp3+ regulatory T cells

2020 ◽  
Vol 6 (40) ◽  
pp. eaba6584
Author(s):  
Tianzhen He ◽  
De Yang ◽  
Xiao-Qing Li ◽  
Mengmeng Jiang ◽  
Md Sahidul Islam ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Antigen Presenting Cells ◽  
Surface Expression ◽  
Pore Channel ◽  
Dependent Manner ◽  
Antigen Presenting

CD4+Foxp3+ regulatory T cells (Tregs) are pivotal for the inhibition of autoimmune inflammatory responses. One way to therapeutically harness the immunosuppressive actions of Tregs is to stimulate the proliferative expansion of TNFR2-expressing CD4+Foxp3+ Tregs via transmembrane TNF (tmTNF). Here, we report that two-pore channel (TPC) inhibitors markedly enhance tmTNF expression on antigen-presenting cells. Furthermore, injection of TPC inhibitors including tetrandrine, or TPC-specific siRNAs in mice, increases the number of Tregs in a tmTNF/TNFR2-dependent manner. In a mouse colitis model, inhibition of TPCs by tetrandrine markedly attenuates colon inflammation by expansion of Tregs. Mechanistically, we show that TPC inhibitors enhance tmTNF levels by disrupting surface expression of TNF-α–converting enzyme by regulating vesicle trafficking. These results suggest that the therapeutic potential of TPC inhibitors is mediated by expansion of TNFR2-expressing Tregs and elucidate the basis of clinical use in the treatment of autoimmune and other inflammatory diseases.

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