scholarly journals Identification of Sulfavant A as the First Synthetic TREM2 Ligand Discloses a Homeostatic Response of Dendritic Cells After Receptor Engagement

2022 ◽  
Author(s):  
Carmela Gallo ◽  
Emiliano Manzo ◽  
Giusi Barra ◽  
Laura Fioretto ◽  
Marcello Ziaco ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Class Ii ◽  
Receptor Activation ◽  
T Cell Response ◽  
Adjuvant Effect ◽  
Adjuvant Activity

Abstract The immune response arises from a fine balance of cellular and molecular mechanisms that provide for surveillance, tolerance, and elimination of dangers as pathogens. Improving the quality of the immune response remains a major goal in immunotherapy and vaccine development. Sulfavant A (SULF A) is a sulfolipid that has shown promising adjuvant activity in a cancer vaccine model. Here we report that SULF A is the first synthetic small molecule binding to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2). The receptor engagement initiates an unconventional maturation of Dendritic cells (DCs) leading to upregulation of the Major Histocompatibility Complex class II (MHC Class II) and costimulatory molecules (CD83, CD86, DC54) without release of T helper type 1 (Th1) or 2 (Th2) cytokines. According to a TREM2 mechanism, this response is mediated by SYK-NFAT axis and is compromised by blockade and gene silencing of the receptor. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and induced interleukin-10 (IL-10) release after lipopolysaccharide (LPS) stimulation. These results well support the adjuvant effect of SULF A and offer novel insights into the role of TREM2 in the differentiation of an unprecedented DC phenotype (homeDCs) that contributes to the maintenance of immune homeostasis without compromising lymphocyte activation and immunogenic response. The biological function of SULF-A may be of interest in various physiological and pathological processes involving the immune system.

Decreased expression of MHC class II and cathepsin E in dendritic cells might contribute to impaired induction of antigen-specific T cell response in NC/Nga mice

2012 ◽  
Vol 59 (1,2) ◽  
pp. 95-101 ◽  
Author(s):  
Tohru Sakai ◽  
Emi Shuto ◽  
Tomoyo Taki ◽  
Honami Imamura ◽  
Miku Kioka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Response ◽  
Class Ii ◽  
T Cell Response ◽  
Cathepsin E

Benfotiamine reduces dendritic cell inflammatory potency

2020 ◽  
Vol 20 ◽  
Author(s):  
Neda Djedovic ◽  
Iva Božić ◽  
Đorđe Miljković ◽  
Irena Lavrnja
Keyword(s):  
Cell Culture ◽  
Bone Marrow ◽  
Immune Response ◽  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Morphological Changes ◽  
Marrow Cell ◽  
Class Ii ◽  
Immunofluorescent Staining ◽  
Mhc Class Ii Molecules

Background: Benfotiamine is a synthetic liposoluble derivative of vitamin B1 that has been shown to have antiinflammatory properties. Objective: To study the effects of benfotiamine on dendritic cells. Methods: Dendritic cells were obtained from murine bone marrow precursor cells in the presence of GM-CSF. Benfotiamine was applied to the cell culture during the process of bone marrow cell differentiation into dendritic cells. Dendritic cells were stimulated with lipopolysaccharide (LPS) and expression of MHC class II molecules and CD86 was determined by flow cytometry, while levels of tumor necrosis factor (TNF) and interleukin (IL)-1β in cell culture supernatants were measured by ELISA. F-Actin, NF-κB and Nrf2 were visualized by immunofluorescent staining and microscopy. Results: Benfotiamine potently reduced LPS-induced expression of MHC class II molecules and CD86, in addition to suppressing the release of pro-inflammatory cytokines TNF and IL-1β. It also prevented LPS-imposed morphological changes of dendritic cells, i.e. enlargement and intensified protrusions. The effects were paralleled with the reduction of NF-κB translocation to the nucleus, but not of Nrf2 activation inhibition. Conclusion: Having in mind the importance of dendritic cells for the configuration of the immune response, our results imply that benfotiamine has the ability to regulate the immune response through inhibition of inflammatory properties of dendritic cells.

scholarly journals CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10–driven MARCH1-mediated ubiquitination and degradation

2011 ◽  
Vol 208 (1) ◽  
pp. 149-165 ◽  
Author(s):  
Lina E. Tze ◽  
Keisuke Horikawa ◽  
Heather Domaschenz ◽  
Debbie R. Howard ◽  
Carla M. Roots ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Molecular Mechanisms ◽  
Costimulatory Molecule ◽  
Class Ii ◽  
Interleukin 10 ◽  
Effective Vaccine ◽  
Vaccine Adjuvants ◽  
Mhc Ii ◽  
Tm Domain

Effective vaccine adjuvants must induce expression of major histocompatability (MHC) class II proteins and the costimulatory molecule CD86 on dendritic cells (DCs). However, some adjuvants elicit production of cytokines resulting in adverse inflammatory consequences. Development of agents that selectively increase MHC class II and CD86 expression without triggering unwanted cytokine production requires a better understanding of the molecular mechanisms influencing the production and degradation of MHC class II and CD86 in DCs. Here, we investigate how CD83, an immunoglobulin protein expressed on the surface of mature DCs, promotes MHC class II and CD86 expression. Using mice with an N-ethyl-N-nitrosourea–induced mutation eliminating the transmembrane (TM) region of CD83, we found that the TM domain of CD83 enhances MHC class II and CD86 expression by blocking MHC class II association with the ubiquitin ligase MARCH1. The TM region of CD83 blocks interleukin 10–driven, MARCH1-dependent ubiquitination and degradation of MHC class II and CD86 in DCs. Exploiting this posttranslational pathway for boosting MHC class II and CD86 expression on DCs may provide an opportunity to enhance the immunogenicity of vaccines.

scholarly journals Nanotechnology-Based Vaccines for Allergen-Specific Immunotherapy: Potentials and Challenges of Conventional and Novel Adjuvants under Research

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 237 ◽  
Author(s):  
Litty Johnson ◽  
Albert Duschl ◽  
Martin Himly
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Specific Immunotherapy ◽  
Vaccine Development ◽  
Symptomatic Treatment ◽  
Treatment Method ◽  
In Vivo Studies ◽  
Adjuvant Effect ◽  
Allergen Specific Immunotherapy

The increasing prevalence of allergic diseases demands efficient therapeutic strategies for their mitigation. Allergen-specific immunotherapy (AIT) is the only causal rather than symptomatic treatment method available for allergy. Currently, AIT is being administered using immune response modifiers or adjuvants. Adjuvants aid in the induction of a vigorous and long-lasting immune response, thereby improving the efficiency of AIT. The successful development of a novel adjuvant requires a thorough understanding of the conventional and novel adjuvants under development. Thus, this review discusses the potentials and challenges of these adjuvants and their mechanism of action. Vaccine development based on nanoparticles is a promising strategy for AIT, due to their inherent physicochemical properties, along with their ease of production and ability to stimulate innate immunity. Although nanoparticles have provided promising results as an adjuvant for AIT in in vivo studies, a deeper insight into the interaction of nanoparticle–allergen complexes with the immune system is necessary. This review focuses on the methods of harnessing the adjuvant effect of nanoparticles by detailing the molecular mechanisms underlying the immune response, which includes allergen uptake, processing, presentation, and induction of T cell differentiation.

scholarly journals Mechanisms of mouse spleen dendritic cell function in the generation of influenza-specific, cytolytic T lymphocytes.

1992 ◽  
Vol 176 (2) ◽  
pp. 519-529 ◽  
Author(s):  
R Nonacs ◽  
C Humborg ◽  
J P Tam ◽  
R M Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Cell Function ◽  
Class Ii ◽  
T Cell Response ◽  
Class I

We have evaluated the capacity of dendritic cells to function as antigen-presenting cells (APCs) for influenza and have examined their mechanism of action. Virus-pulsed dendritic cells were 100 times more efficient than bulk spleen cells in stimulating cytotoxic T lymphocyte (CTL) formation. The induction of CTLs required neither exogenous lymphokines nor APCs in the responding T cell population. Infectious virus entered dendritic cells through intracellular acidic vacuoles and directed the synthesis of several viral proteins. If ultraviolet (UV)-inactivated or bromelain-treated viruses were used, viral protein synthesis could not be detected, and there was poor induction of CTLs. This indicated that dendritic cells were not capable of processing noninfectious virus onto major histocompatibility complex (MHC) class I molecules. However, UV-inactivated and bromelain-treated viruses were presented efficiently to class II-restricted CD4+ T cells. The CD4+ T cells crossreacted with different strains of influenza and markedly amplified CTL formation. Cell lines that lacked MHC class II, and consequently the capacity to stimulate CD4+ T cells, failed to induce CTLs unless helper lymphokines were added. Similarly, dendritic cells pulsed with the MHC class I-restricted nucleoprotein 147-155 peptide were poor stimulators in the absence of exogenous helper factors. We conclude that the function of dendritic cells as APCs for the generation of virus-specific CTLs in vitro depends measurably upon: (a) charging class I molecules with peptides derived from endogenously synthesized viral antigens, and (b) stimulating a strong CD4+ helper T cell response.

Dendritic Cells as a Novel Target for Erythropoietin: Studies in Murine Models.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2417-2417
Author(s):  
Lilach Lifchitz ◽  
Sari Prutchi Sagiv ◽  
Maayan Markovitz ◽  
Moshe Mittelman ◽  
Drorit Newmann
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Surface Expression ◽  
Class Ii ◽  
Mapk Signaling ◽  
Target Cells ◽  
Erythroid Progenitor

Abstract Erythropoietin (EPO) is the major hormone that promotes the proliferation and differentiation of erythroid progenitor cells. Unexpectedly, EPO receptor (EPO-R) was also found on non-erythroid cells; thus leading to the discovery of non-erythroid effects of EPO. Our own previous contribution to that issue was in demonstrating that the immune system is a target for EPO, including both the cellular and humoral immune response types. As yet, the direct target cells for EPO as well as the molecular mechanisms underlying its function as an immunomodulator remain unknown. We first examined lymphocytes as possible candidates, and could not detect any expression of EPO-Rs on these cells. Here, we focused on dendritic cells (DCs), known to initiate immune response as antigen presenting and T cell priming cells. We employed murine bone marrow DCs (BMDCs) and splenic DCs (SDCs) models to determine EPO-R expression, and delineate in-vitro and in-vivo effects of EPO via these cells. We found that BMDCs express EPO-R mRNA, as detected by RT-PCR. In vitro stimulation of the BMDCs with recombinant human EPO (rHuEPO) activated the NFkB and MAPK signaling pathways, and induced a higher surface expression of CD80, CD86 and MHC class II. These data are reinforced by in vivo experiments, showing that rHuEPO injection into naïve mice led to an increase in the SDC population and in the cell surface expression of CD80, CD86 and MHC class II markers. These novel findings implicate the significance of the multifunctional role of EPO in the hematopoietic and immune systems, and may lead to its further clinical applications as an immunomodulator.

MHC Sınıf I ve MHC Sınıf II Gen Düzenlenmesi

2020 ◽  
Vol 8 (3) ◽  
pp. 144-156
Author(s):  
Şule KARATAŞ ◽  
Fatma SAVRAN OĞUZ
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Gene Regulation ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Class I ◽  
Mhc Molecules ◽  
Class Ii Mhc ◽  
Regulation Mechanisms

Introduction: Peptides obtained by processing intracellular and extracellular antigens are presented to T cells to stimulate the immune response. This presentation is made by peptide receptors called major histocompatibility complex (MHC) molecules. The regulation mechanisms of MHC molecules, which have similar roles in the immune response, especially at the gene level, have significant differences according to their class. Objective: Class I and class II MHC molecules encoded by MHC genes on the short arm of the sixth chromosome are peptide receptors that stimulate T cell response. These peptides, which will enable the recognition of the antigen from which they originate, are loaded into MHC molecules and presented to T cells. Although the principles of loading and delivering peptides are similar for both molecules, the peptide sources and peptide loading mechanisms are different. In addition, class I molecules are expressed in all nucleated cells while class II molecules are expressed only in Antigen Presentation Cells (APC). These differences; It shows that MHC class I is not expressed by exactly the same transcriptional mechanisms as MHC class II. In our article, we aimed to compare the gene expressions of both classes and reveal their similarities and differences. Discussion and Conclusion: A better understanding of the transcriptional mechanisms of MHC molecules will reveal the role of these molecules in diseases more clearly. In our review, we discussed MHC gene regulation mechanisms with presence of existing informations, which is specific to the MHC class, for contribute to future research. Keywords: MHC class I, MHC class II, MHC gene regulation, promoter, SXY module, transcription

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