scholarly journals Immunostimulatory Potential of Extracellular Vesicles Isolated from an Edible Plant, Petasites japonicus, via the Induction of Murine Dendritic Cell Maturation

2021 ◽  
Vol 22 (19) ◽  
pp. 10634
Author(s):  
Jeong Moo Han ◽  
Ha-Yeon Song ◽  
Seung-Taik Lim ◽  
Kwang-Il Kim ◽  
Ho Seong Seo ◽  
...  
Keyword(s):  
T Cells ◽  
Extracellular Vesicles ◽  
Dendritic Cell Maturation ◽  
Signal Pathways ◽  
Edible Plant ◽  
Antigen Uptake ◽  
Mhc I ◽  
Average Size ◽  
Antigen Presenting ◽  
Petasites Japonicus

Extracellular vesicles (EVs) have recently been isolated from different plants. Plant-derived EVs have been proposed as potent therapeutics and drug-delivery nanoplatforms for delivering biomolecules, including proteins, RNAs, DNAs, and lipids. Herein, Petasites japonicus-derived EVs (PJ-EVs) were isolated through a series of centrifugation steps and characterized using dynamic light scattering and transmission electron microscopy. Immunomodulatory effects of PJ-EVs were assessed using dendritic cells (DCs). PJ-EVs exhibited a spherical morphology with an average size of 122.6 nm. They induced the maturation of DCs via an increase in the expression of surface molecules (CD80, CD86, MHC-I, and MHC-II), production of Th1-polarizing cytokines (TNF-α and IL-12p70), and antigen-presenting ability; however, they reduced the antigen-uptake ability. Furthermore, maturation of DCs induced by PJ-EVs was dependent on the activation and phosphorylation of MAPK and NF-κB signal pathways. Notably, PJ-EV-treated DCs strongly induced the proliferation and differentiation of naïve T cells toward Th1-type T cells and cytotoxic CD8+ T cells along with robust secretion of IFN-γ and IL-2. In conclusion, our study indicates that PJ-EVs can be potent immunostimulatory candidates with an ability of strongly inducing the maturation of DCs.

Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 3171-3176 ◽  
Author(s):  
Susanne Auffermann-Gretzinger ◽  
Emmet B. Keeffe ◽  
Shoshana Levy
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Dendritic Cell Maturation ◽  
Tumor Formation ◽  
Hcv Infection ◽  
Surface Markers ◽  
Antigen Uptake ◽  
Healthy Donors ◽  
Antigen Presenting

Abstract Dendritic cells (DCs) are important for the initiation of immune responses to foreign antigens. Their antigen uptake and presentation capacities enable them to prime and activate T cells. Immature DCs capture antigens; however, they must be activated to mature before serving as efficient antigen-presenting cells. The antigen-presenting capacity of DCs can be diminished during viral infection and as a consequence of tumor formation. Chronic infection with hepatitis C virus (HCV) has been shown to affect the allostimulatory function of DCs. In this study, it is demonstrated that monocyte-derived DCs from patients with chronic HCV infection do not respond to maturation stimuli. Instead, they maintain their immature phenotype, reflected by the pattern of cell surface markers and by their continued capacity to uptake antigen. Moreover, their allostimulatory abilities are impaired compared with those of mature DCs derived from healthy donors. To investigate a possible correlation between viral clearance and this DC maturation defect, patients with resolved HCV infection after a course of antiviral therapy were studied. Results demonstrate that DCs from patients who cleared HCV behaved like DCs from healthy donors: in response to maturation stimuli, they decrease antigen uptake, up-regulate expression of appropriate surface markers, and are potent stimulators of allogeneic T cells.

scholarly journals Presentation of Toxoplasma gondii Antigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells

2007 ◽  
Vol 75 (11) ◽  
pp. 5200-5209 ◽  
Author(s):  
Florence Dzierszinski ◽  
Marion Pepper ◽  
Jason S. Stumhofer ◽  
David F. LaRosa ◽  
Emma H. Wilson ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Antigen Processing ◽  
Cell Types ◽  
T Cell Response ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Antigen Presenting

ABSTRACT Challenge with the intracellular protozoan parasite Toxoplasma gondii induces a potent CD8+ T-cell response that is required for resistance to infection, but many questions remain about the factors that regulate the presentation of major histocompatibility complex class I (MHC-I)-restricted parasite antigens and about the role of professional and nonprofessional accessory cells. In order to address these issues, transgenic parasites expressing ovalbumin (OVA), reagents that track OVA/MHC-I presentation, and OVA-specific CD8+ T cells were exploited to compare the abilities of different infected cell types to stimulate CD8+ T cells and to define the factors that contribute to antigen processing. These studies reveal that a variety of infected cell types, including hematopoietic and nonhematopoietic cells, are capable of activating an OVA-specific CD8+ T-cell hybridoma, and that this phenomenon is dependent on the transporter associated with antigen processing and requires live T. gondii. Several experimental approaches indicate that T-cell activation is a consequence of direct presentation by infected host cells rather than cross-presentation. Surprisingly, nonprofessional antigen-presenting cells (APCs) were at least as efficient as dendritic cells at activating this MHC-I-restricted response. Studies to assess whether these cells are involved in initiation of the CD8+ T-cell response to T. gondii in vivo show that chimeric mice expressing MHC-I only in nonhematopoietic compartments are able to activate OVA-specific CD8+ T cells upon challenge. These findings associate nonprofessional APCs with the initial activation of CD8+ T cells during toxoplasmosis.

First Generation Chimeric Antigen Receptor Display Functional Defects In Key Signal Pathways Upon Antigen Stimulation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2088-2088
Author(s):  
Johannes Duell ◽  
Sarah Lurati ◽  
Marcus Dittrich ◽  
Tanja Bedke ◽  
Martin Pule ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Target Cell ◽  
First Generation ◽  
Cytokine Production ◽  
Receptor Expression ◽  
Signal Pathways ◽  
Mhc I ◽  
Split Anergy

Abstract Abstract 2088 Introduction: A promising strategy for tumor therapy is the adoptive transfer of tumor specific T cells which are endowed with chimeric antigen receptors (CAR). First generation CARs are constructed by single chain antibodies and as signal domain the ζ chain of the CD3 complex. However, clinical trials are disappointing as adoptive transferred T-cells showed only modest persistence in patients resulting in limited clinical activity. We there for hypothesized that CAR expressing T-cells in comparison to unmodified T-cells display signaling defects when stimulated via their CARs. Methods: Cytomegalovirus(CMV)pp65 MHC I restricted CD8+ T-cells were generated, isolated by tetramer selection and modified with first generation CAR targeting CD19 and purified based on their receptor expression to more than > 95% purity. T-cell receptor (TCR) and CAR expression were quantified by Quantibright beads. Effector function of both T-cell populations were analyzed for specific lysis, cytokine production (IFN-g, TNF-a) and proliferation (CSFE) upon target cell stimulation. Phosphorylation of Erk, Jnk, p38 and PLC-γ was measured and analyzed with CBA Flexsets from BD. All statistical analyses have been performed using the statistical software package R. Signal peak intensities have been compared using the nonparametric wilcoxon rank sum test. Results: CMV-specific MHC-I restricted TCR as well as the CARs are expressed at same density levels and T-cells show equally lysis of targets either in the time of lysis onset as well the maximal lysis. In contrast, cytokine production (IFN, TNF-a) as well as antigen driven proliferation was reduced in CAR expressing T-cells when compared to CMV-specific CD8+ T-cells upon target exposure. PLC-γ was phosphorylated within minutes after target contact by CMV-specific CD8+ T-cells whereas CAR transduced CMV-specific CD8+ T-cells showed no significant phosphorylation of PLC-γ to target cell exposure. T-cell activated via CAR's demonstrated a statistically significant reduction of maximal phosphorylation in comparison to CMV-specific T-cells for ERK, for JNK and for p38. To exclude that CAR modification of CMV-specific CD8+ T-cells may impair signaling, CAR-CMV-specific CD8+ T-cells were exposed to CMVpp65 expressing targets. Killing, cytokine production and signal intensity were restored in comparison to parental CMV-specific CD8+ T-cells. Conclusion: CAR expressing T-cells show functionally signs of split anergy by efficient target elimination but fails to produce significant levels of cytokines and do not proliferate in response to target stimulation. Split anergy is not due to reduced expression of the CAR's but due to a complete lack of phosphorylation of PLC-γ as well as reduced phosphorylation of MAP-kinases ERK, p38 and JNK. These results potentially explain why primary CAR expressing T-cells fail to show significant clinical efficacy. Analysis of adequate phosphorylation, as proposed here, may be a powerful tool to identify the most promising second generation CARs for clinical studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Engineering Vaccines to Reprogram Immunity against Head and Neck Cancer

2018 ◽  
Vol 97 (6) ◽  
pp. 627-634 ◽  
Author(s):  
Y.S. Tan ◽  
K. Sansanaphongpricha ◽  
M.E.P. Prince ◽  
D. Sun ◽  
G.T. Wolf ◽  
...  
Keyword(s):  
T Cells ◽  
Head And Neck ◽  
Cancer Vaccines ◽  
Immune Escape ◽  
Cell Repertoire ◽  
Antigen Uptake ◽  
Immune Priming ◽  
Extensive Collection ◽  
Checkpoint Receptors ◽  
Antigen Presenting

The recent Food and Drug Administration’s approval of monoclonal antibodies targeting immune checkpoint receptors (ICRs) for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) offers exciting promise to improve patient outcome and reduce morbidities. A favorable response to ICR blockade relies on an extensive collection of preexisting tumor-specific T cells in the tumor microenvironment (TME). ICR blockade reinvigorates exhausted CD8+ T cells and enhances immune killing. However, resistance to ICR blockade is observed in about 85% of patients with HNSCC, therefore highlighting the importance of characterizing the mechanisms underlying HNSCC immune escape and exploring combinatorial strategies to sensitize hypoimmunogenic cold HNSCC to ICR inhibition. Cancer vaccines are designed to bypass the cold TME and directly deliver cancer antigens to antigen-presenting cells (APCs); these vaccines epitomize a priming strategy to synergize with ICR inhibitors. Cancer cells are ineffective antigen presenters, and poor APC infiltration as well as the M2-like polarization in the TME further dampens antigen uptake and processing, both of which render ineffective innate and adaptive immune detection. Cancer vaccines directly activate APC and expand the tumor-specific T-cell repertoire. In addition, cancer vaccines often contain an adjuvant, which further improves APC function, promotes epitope spreading, and augments host intrinsic antitumor immunity. Thus, the vaccine-induced immune priming generates a pool of effectors whose function can be enhanced by ICR inhibitors. In this review, we summarize the major HNSCC immune evasion strategies, the ongoing effort toward improving HNSCC vaccines, and the current challenges limiting the efficacy of cancer vaccines.

scholarly journals Surface-bound antigen induces B-cell permeabilization and lysosome exocytosis facilitating antigen uptake and presentation to T-cells

2020 ◽  
Author(s):  
Fernando Y. Maeda ◽  
Jurriaan J. H. van Haaren ◽  
David B. Langley ◽  
Daniel Christ ◽  
Norma W. Andrews ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Lipid Bilayers ◽  
Cell Receptor ◽  
Cell Permeabilization ◽  
Antigen Uptake ◽  
Extracellular Release ◽  
Antigen Presenting ◽  
Muscle Myosin

AbstractB-cell receptor (BCR)-mediated antigen internalization and presentation are essential for humoral memory immune responses. Antigen encountered by B-cells is often tightly associated with the surface of pathogens and/or antigen-presenting cells. Internalization of such antigens requires myosin-mediated traction forces and extracellular release of lysosomal enzymes, but the mechanism triggering lysosomal exocytosis is unknown. Here we show that BCR-mediated high-affinity recognition of antigen tethered to beads or planar lipid-bilayers causes localized plasma membrane (PM) permeabilization, a process that requires BCR signaling and non-muscle myosin II activity. B-cell permeabilization triggers a PM repair response involving lysosomal exocytosis. B-cells transiently permeabilized by surface-associated antigen internalize more antigen than cells that remain intact, and higher affinity antigens that cause more B-cell permeabilization and lysosomal exocytosis are more efficiently presented to T-cells. Thus, PM permeabilization by surface-associated antigen triggers a lysosome-mediated B-cell resealing response, which provides the extracellular hydrolases that can facilitate antigen internalization and presentation.

A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1

Science ◽  
2019 ◽  
Vol 366 (6472) ◽  
pp. 1522-1527 ◽  
Author(s):  
Jérôme Le Nours ◽  
Nicholas A. Gherardin ◽  
Sri H. Ramarathinam ◽  
Wael Awad ◽  
Florian Wiede ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptors ◽  
Γδ T Cells ◽  
Mhc I ◽  
Cell Receptors ◽  
Histocompatibility Complex ◽  
Antigen Complex ◽  
Binding Cleft ◽  
Antigen Presenting

T cell receptors (TCRs) recognize antigens presented by major histocompatibility complex (MHC) and MHC class I–like molecules. We describe a diverse population of human γδ T cells isolated from peripheral blood and tissues that exhibit autoreactivity to the monomorphic MHC-related protein 1 (MR1). The crystal structure of a γδTCR–MR1–antigen complex starkly contrasts with all other TCR–MHC and TCR–MHC-I-like complex structures. Namely, the γδTCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 α3 domain. A similar pattern of reactivity was observed for diverse MR1-restricted γδTCRs from multiple individuals. Accordingly, we simultaneously report MR1 as a ligand for human γδ T cells and redefine the parameters for TCR recognition.

scholarly journals Ligation of Major Histocompatability Complex (MHC) Class I Molecules on Human T Cells Induces Cell Death through PI-3 Kinase–induced c-Jun NH2-terminal Kinase Activity: A Novel Apoptotic Pathway Distinct from Fas-induced Apoptosis

1997 ◽  
Vol 139 (6) ◽  
pp. 1523-1531 ◽  
Author(s):  
Søren Skov ◽  
Pia Klausen ◽  
Mogens H. Claesson
Keyword(s):  
T Cells ◽  
Kinase Activity ◽  
Dominant Negative ◽  
Class I ◽  
Signal Pathways ◽  
Major Histocompatability Complex ◽  
Jurkat T Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Induced Apoptosis

Ligation of major histocompatability complex class I (MHC-I) molecules expressed on T cells leads to both growth arrest and apoptosis. The aim of the current study was to investigate the intracellular signal pathways that mediate these effects. MHC-I ligation of human Jurkat T cells induced a morphologically distinct form of apoptosis within 6 h. A specific caspase inhibitor, which inhibited Fas-induced apoptosis, did not affect apoptosis induced by MHC-I ligation. Furthermore, MHC-I–induced apoptosis did not involve cleavage and activation of the poly(ADP- ribose) polymerase (PARP) endonuclease or degradation of genomic DNA into the typical fragmentation ladder, both prominent events of Fas-induced apoptosis. These results suggest that MHC-I ligation of Jurkat T cells induce apoptosis through a signal pathway distinct from the Fas molecule. In our search for other signal pathways leading to apoptosis, we found that the regulatory 85-kD subunit of the phosphoinositide-3 kinase (PI-3) kinase was tyrosine phosphorylated after ligation of MHC-I and the PI-3 kinase inhibitor wortmannin selectively blocked MHC-I–, but not Fas-induced, apoptosis. As the c-Jun NH2-terminal kinase (JNK) can be activated by PI-3 kinase activity, and has been shown to be involved in apoptosis of lymphocytes, we examined JNK activation after MHC-I ligation. Strong JNK activity was observed after MHC-I ligation and the activity was completely blocked by wortmannin. Inhibition of JNK activity, by transfecting cells with a dominant-negative JNKK– MKK4 construct, led to a strong reduction of apoptosis after MHC-I ligation. These results suggest a critical engagement of PI-3 kinase–induced JNK activity in apoptosis induced by MHC-I ligation.

scholarly journals Annona muricata L.-Derived Polysaccharides as a Potential Adjuvant to a Dendritic Cell-Based Vaccine in a Thymoma-Bearing Model

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1602 ◽  
Author(s):  
Woo Sik Kim ◽  
Jeong Moo Han ◽  
Ha-Yeon Song ◽  
Eui-Hong Byun ◽  
Seung-Taik Lim ◽  
...  
Keyword(s):  
T Cells ◽  
Bacterial Infections ◽  
Annona Muricata ◽  
Adjuvant Effect ◽  
Antigen Uptake ◽  
Surface Molecules ◽  
Antigen Presenting ◽  
Anti Tumor Activity ◽  
Dc Maturation

Dendritic cells (DCs) are powerful antigen-presenting cells that are often used to evaluate adjuvants, particularly for adjuvant selection for various vaccines. Here, polysaccharides (named ALP) isolated from leaves of Annona muricata L., which are used in traditional medicine such as for bacterial infections and inflammatory diseases, were evaluated as an adjuvant candidate that can induce anti-tumor activity. We first confirmed the phenotypic (surface molecules, cytokines, antigen uptake, and antigen-presenting ability) and functional alterations (T cell proliferation/activation) of DCs in vitro. We also confirmed the adjuvant effect by evaluating anti-tumor activity and immunity using an ALP-treated DC-immunized mouse model. ALP functionally induced DC maturation by up-regulating the secretion of Th1-polarizing pro-inflammatory cytokines, the expression of surface molecules, and antigen-presenting ability. ALP triggered DC maturation, which is dependent on the activation of the MAPK and NF-κB signaling pathways. ALP-activated DCs showed an ample capacity to differentiate naive T cells to Th1 and activated CD8+ T cells effectively. The systemic administration of DCs that pulse ALP and ovalbumin peptides strongly increased cytotoxic T lymphocyte (CTL) activity (by 9.5% compared to that in the control vaccine groups), the generation of CD107a-producing multifunctional T cells, and Th1-mediated humoral immunity, and caused a significant reduction (increased protection by 29% over that in control vaccine groups) in tumor growth. ALP, which triggers the Th1 and CTL response, provides a basis for a new adjuvant for various vaccines.

scholarly journals Revisiting the Antigen-Presenting Function of β Cells in T1D Pathogenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yang Li ◽  
Fei Sun ◽  
Tian-Tian Yue ◽  
Fa-Xi Wang ◽  
Chun-Liang Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cell Damage ◽  
Cellular Level ◽  
Stressed Condition ◽  
Β Cells ◽  
Β Cell ◽  
Mhc I ◽  
Autoimmune Attack ◽  
Antigen Presenting

Type 1 diabetes (T1D) is characterized by the unresolved autoimmune inflammation and islet β cell destruction. The islet resident antigen-presenting cells (APCs) including dendritic cells and macrophages uptake and process the β cell-derived antigens to prime the autoreactive diabetogenic T cells. Upon activation, those autoreactive T cells produce copious amount of IFN-γ, TNF-α and IL-1β to induce β cell stress and death. Autoimmune attack and β cell damage intertwine together to push forward this self-destructive program, leading to T1D onset. However, β cells are far beyond a passive participant during the course of T1D development. Herein in this review, we summarized how β cells are actively involved in the initiation of autoimmune responses in T1D setting. Specifically, β cells produce modified neoantigens under stressed condition, which is coupled with upregulated expression of MHC I/II and co-stimulatory molecules as well as other immune modules, that are essential properties normally exhibited by the professional APCs. At the cellular level, this subset of APC-like β cells dynamically interacts with plasmacytoid dendritic cells (pDCs) and manifests potency to activate autoreactive CD4 and CD8 T cells, by which β cells initiate early autoimmune responses predisposing to T1D development. Overall, the antigen-presenting function of β cells helps to explain the tissue specificity of T1D and highlights the active roles of structural cells played in the pathogenesis of various immune related disorders.

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