LIGHT, a TNF-Like Molecule, Costimulates T Cell Proliferation and Is Required for Dendritic Cell-Mediated Allogeneic T Cell Response

Abstract Background Autoimmune hepatitis (AIH) is a T cell-mediated immune disease that activates abnormally against hepatic antigens. We have previously reported that endometrial regenerative cells (ERCs) were a novel source of adult stem cells, which exhibiting with powerful immunomodulatory effects. Galectin-9 (Gal-9) is expressed in ERCs and plays an important role in regulating T cell response. This study aims to explore the role of ERCs in attenuation of AIH and to determine the potential mechanism of Gal-9 in ERC-mediated immune regulation. Methods ERCs were obtained from menstrual blood of healthy female volunteers. In vitro, ERCs were transfected with lentivirus vectors carrying LGALS9 gene and encoding green fluoresce protein (GFP-Gal-9-LVs) at a MOI 50, Gal-9 expression in ERCs was detected by ELISA and Q-PCR. CD4+ T cells isolated from C57BL/6 mouse spleen were co-cultured with ERCs. The proliferation of CD4+ T cells was detected by CCK-8 kit and the level of Lck/zap-70/LAT protein was measured by western blot. Furthermore, AIH was induced by ConA in C57BL/6 mice which were randomly assigned to untreated, unmodified ERC-treated and Gal-9 high-expressing ERC-treated groups. Histopathological score, liver function, CD4+/CD8+ cell infiltration in liver tissues, the proportion of immune cells in the spleen and liver, and ERC tracking were performed accordingly to assess the progression degree of AIH. Results After transfecting with GFP-Gal-9-LVs, Gal-9 expression in ERCs was significantly increased. Additionally, Gal-9 high-expressing ERCs effectively inhibited CD4+ T cell proliferation and downregulated CD4+ T cell active related proteins p-Lck/p-ZAP70/p-LAT in vitro. Furthermore, treatment with Gal-9 high-expressing ERCs restored liver function, ameliorated liver pathological damage, inhibit CD4+ and CD8+ T cell proliferation and suppress Th1 and Th17 cell response in the hepatitis mice. In addition, Gal-9 high-expressing ERCs further markedly enhanced the level of IL-10 but reduced the levels of IFN-γ, TNF-α, and IL-4 in mouse sera and liver. Cell tracking also showed that ERCs could migrate to the damaged liver organs. Conclusions The results suggested that Gal-9 was an essential modulator, which was required by ERCs in regulating T cell response and attenuating ConA-induced experimental hepatitis. And also, it provides a novel idea for the clinical treatment of AIH.

Download Full-text

Direct Presentation Regulates the Magnitude of the CD8+T Cell Response to Cell-Associated Antigen through Prolonged T Cell Proliferation

The Journal of Immunology ◽

10.4049/jimmunol.0903920 ◽

2010 ◽

Vol 185 (5) ◽

pp. 2763-2772 ◽

Cited By ~ 5

Author(s):

Angela M. Tatum ◽

Alan M. Watson ◽

Todd D. Schell

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

T Cell Proliferation

Download Full-text

Direct and indirect immune effects of CMP-001, a virus-like particle containing a TLR9 agonist

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002484 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002484

Author(s):

Shakoora A Sabree ◽

Andrew P Voigt ◽

Sue E Blackwell ◽

Ajaykumar Vishwakarma ◽

Michael S Chimenti ◽

...

Keyword(s):

Cell Proliferation ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Secondary Effects ◽

Tlr9 Agonist ◽

Virus Like Particle ◽

Enhanced Expression

BackgroundCMP-001, also known as vidutolimod, is a virus-like particle containing a TLR9 agonist that is showing promise in early clinical trials. Our group previously demonstrated that the immunostimulatory effects of CMP-001 are dependent on an anti-Qβ antibody response which results in opsonization of CMP-001 and uptake by plasmacytoid dendritic cells (pDCs) that then produce interferon (IFN)-α. IFN-α then leads to an antitumor T-cell response that is responsible for the in vivo efficacy of CMP-001. Here, we explore mechanisms by which the initial effects of CMP-001 on pDCs activate other cells that can contribute to development of an antitumor T-cell response.MethodsUptake of CMP-001 by various peripheral blood mononuclear cell (PBMC) populations and response to anti-Qβ-coated CMP-001 were evaluated by flow cytometry and single-cell RNA sequencing. Purified monocytes were treated with anti-Qβ-coated CMP-001 or recombinant IFN-α to evaluate direct and secondary effects of anti-Qβ-coated CMP-001 on monocytes.ResultsMonocytes had the highest per cell uptake of anti-Qβ-coated CMP-001 with lower levels of uptake by pDCs and other cell types. Treatment of PBMCs with anti-Qβ-coated CMP-001 induced upregulation of IFN-responsive genes including CXCL10, PDL1, and indoleamine-2,3-dioxygenase (IDO) expression by monocytes. Most of the impact of anti-Qβ-coated CMP-001 on monocytes was indirect and mediated by IFN-α, but uptake of anti-Qβ-coated CMP-001 altered the monocytic response to IFN-α and resulted in enhanced expression of PDL1, IDO, and CD80 and suppressed expression of CXCL10. These changes included an enhanced ability to induce autologous CD4 T-cell proliferation.ConclusionsAnti-Qβ-coated CMP-001 induces IFN-α production by pDCs which has secondary effects on a variety of cells including monocytes. Uptake of anti-Qβ-coated CMP-001 by monocytes alters their response to IFN-α, resulting in enhanced expression of PDL1, IDO and CD80 and suppressed expression of CXCL10. Despite aspects of an immunosuppressive phenotype, these monocytes demonstrated increased ability to augment autologous CD4 T-cell proliferation. These findings shed light on the complexity of the mechanism of action of anti-Qβ-coated CMP-001 and provide insight into pathways that may be targeted to further enhance the efficacy of this novel approach to immunotherapy.

Download Full-text

Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity

Gut ◽

10.1136/gutjnl-2020-322924 ◽

2021 ◽

pp. gutjnl-2020-322924

Author(s):

Tuxiong Huang ◽

Xiang-Yu Tan ◽

Hui-Si Huang ◽

Yu-Ting Li ◽

Bei-Lei Liu ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Cell Response ◽

T Cell Responses ◽

Tumour Microenvironment ◽

T Cell Response ◽

Cell Responses ◽

Cancer Associated Fibroblast ◽

Anticancer Immunotherapy ◽

Novel Therapeutic Strategies

ObjectiveSolid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC).DesignAnti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses.ResultsA negative correlation between WNT2+ CAFs and active CD8+ T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades.ConclusionsCAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.

Download Full-text

Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7

Stem Cells and Development ◽

10.1089/scd.2016.0009 ◽

2016 ◽

Vol 25 (10) ◽

pp. 774-787 ◽

Cited By ~ 17

Author(s):

Matthew M. Halpert ◽

Vanaja Konduri ◽

Dan Liang ◽

Yunyu Chen ◽

James B. Wing ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

T Lymphocyte ◽

Cell Response ◽

Cytotoxic T Lymphocyte ◽

T Cell Response

Download Full-text

T-cell mediated autoimmunity to the insulinoma-associated protein 2 islet tyrosine phosphatase in type 1 diabetes mellitus

Acta Endocrinologica ◽

10.1530/eje.0.1410272 ◽

1999 ◽

pp. 272-278 ◽

Cited By ~ 12

Author(s):

F Dotta ◽

S Dionisi ◽

V Viglietta ◽

C Tiberti ◽

MC Matteoli ◽

...

Keyword(s):

Cell Proliferation ◽

Type 1 Diabetes ◽

T Cell ◽

T Lymphocyte ◽

Tyrosine Phosphatase ◽

T Cell Response ◽

T Cell Proliferation ◽

Diabetic Patients ◽

Hla Dr

The target molecules of the T-cell response in type 1 diabetes, despite their pathogenic importance, remain largely uncharacterized, especially in humans. Interestingly, molecules such as insulin and glutamic acid decarboxylase (GAD) have been shown to be a target not only of autoantibodies, but also of autoreactive T-lymphocytes both in man and in the non-obese diabetic (NOD) mouse. In the present study we aimed to determine the existence of a specific T-cell response towards the insulinoma-associated protein 2 (IA-2) islet tyrosine phosphatase, a recently identified autoantigen which is the target of autoantibodies strongly associated with diabetes development. Human recombinant IA-2 produced in Escherichia coli, was tested for its reactivity with peripheral blood lymphocytes obtained from 16 newly diagnosed type 1 diabetic patients and from 25 normal controls, 15 of whom were HLA-DR-matched. A T-cell proliferation assay was performed in triplicate employing freshly isolated cells in the absence or in the presence of the antigen to be tested (at two different concentrations: 2 microg/ml and 10 microg/ml). A specific T-cell proliferation (defined as a stimulation index (S.I.) >/=3) was observed against IA-2 used at a concentration of 10 microg/ml (but not of 2 microg/ml) in 8/16 diabetic patients, in 1/15 HLA-DR-matched control subjects (P<0.01 by Fisher exact test) and in 0/10 of the remaining normal individuals. A statistically significant difference (P<0.003 by Mann-Whitney U test) was also observed in S.I. values between patients (3.1+/-1.4) and HLA-DR-matched controls (1.7+/-0.54) employing IA-2 at a concentration of 10 microg/ml. However, when IA-2 was used at a concentration of 2 microg/ml, the difference in S. I. between patients (1.65+/-0.8) and controls (1.0+/-0.3) did not reach statistical significance. In conclusion, these data show the presence of a specific, dose-dependent T-lymphocyte response against the IA-2 islet tyrosine phosphatase at the onset of type 1 diabetes. Consequently, this molecule appears to be a target not only at the B-lymphocyte but also at the T-lymphocyte level, reinforcing the potential pathogenic role of this autoantigen in the islet destructive process.

Download Full-text

Effective cancer immunotherapy by Ganoderma lucidum polysaccharide-gold nanocomposites through dendritic cell activation and memory T cell response

Carbohydrate Polymers ◽

10.1016/j.carbpol.2018.10.028 ◽

2019 ◽

Vol 205 ◽

pp. 192-202 ◽

Cited By ~ 26

Author(s):

Shulei Zhang ◽

Guibin Pang ◽

Chao Chen ◽

Jianzhong Qin ◽

Huan Yu ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Cancer Immunotherapy ◽

Cell Response ◽

Ganoderma Lucidum ◽

Cell Activation ◽

T Cell Response ◽

Dendritic Cell Activation ◽

Memory T Cell ◽

Gold Nanocomposites

Download Full-text

Intrinsic Variability Present in Wharton’s Jelly Mesenchymal Stem Cells and T Cell Responses May Impact Cell Therapy

Stem Cells International ◽

10.1155/2017/8492797 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 10

Author(s):

Fernanda Vieira Paladino ◽

Luiz Roberto Sardinha ◽

Carla Azevedo Piccinato ◽

Anna Carla Goldberg

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Mesenchymal Stem Cells ◽

T Cell ◽

Replicative Senescence ◽

T Cell Response ◽

Wharton’S Jelly ◽

T Cell Proliferation ◽

Intrinsic Variability ◽

Wharton's Jelly

Wharton’s jelly mesenchymal stem cells (WJ-MSC) exhibit immunomodulatory effects on T cell response. WJ-MSC are easy to collect, process, and proliferate rapidly in culture, but information on the variability of individual cell samples impacting upon in vitro expansion, immunomodulatory potential, and aging processes is still lacking. We propose to evaluate the immunomodulatory cytokine profile and capacity to inhibit T cell proliferation of WJ-MSC progressing to replicative senescence in order to analyze if expected responses are affected. Our results show that the gene expression of immunomodulatory molecules varied among samples with no specific pattern present. In coculture, all WJ-MSC were capable of inhibiting mitogen-activated CD3+ T cell proliferation, although to different degrees, and each PBMC responded with a different level of inhibition. Thus, we suggest that each WJ-MSC displays unique behavior, differing in patterns of cytokine mRNA expression and immunomodulatory capacity. We believe that variability between samples may play a role in the effectiveness of WJ-MSC employed therapeutically.

Download Full-text