scholarly journals Street RABV induces the cholinergic anti-inflammatory pathway in human monocyte-derived macrophages by binding to nAChr ɑ7, and upregulates the M2-c marker CD163

2021 ◽  
Author(s):  
C.W.E. Embregts ◽  
L. Begeman ◽  
C.J. Voesenek ◽  
B.E.E. Martina ◽  
M.P.G. Koopmans ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Human Monocyte ◽  
T Cell Proliferation ◽  
Strong Immune Response ◽  
Inflammatory Pathway ◽  
Inflammatory State ◽  
The Central Nervous System ◽  
Anti Inflammatory ◽  
Antigen Presenting

AbstractRabies virus (RABV) is able to reach the central nervous system (CNS) without triggering a strong immune response, using multiple mechanisms to evade and suppress the host immune system. After infection via a bite or scratch from a rabid animal, RABV comes into contact with macrophages, which are the first antigen-presenting cells (APCs) that are recruited to the area and play an essential role in the onset of a specific immune response. It is poorly understood how RABV affects macrophages, and if the interaction contributes to the observed immune suppression. This study was undertaken to characterize the interactions between RABV and human monocyte-derived macrophages (MDMs). We showed that street RABV does not replicate in human MDMs. Using a recombinant trimeric RABV glycoprotein (RABV-tG) we showed binding to the nicotinic acetylcholine receptor alpha 7 (nAChr ɑ7) on MDMs, and confirmed the specificity using the nAChr ɑ7 antagonist alpha-bungarotoxin (ɑ-BTX). We found that this binding induced the cholinergic anti-inflammatory pathway (CAP), characterized by a significant decrease in tumor necrosis factor ɑ (TNF-ɑ) upon LPS challenge. Using confocal microscopy we found that induction of the CAP is associated with significant cytoplasmic retention of nuclear factor κB (NF-κB). Co-cultures of human MDMs exposed to street RABV and autologous T cells further revealed that the observed suppression of MDMs affects their function as T cell activators as well, as we found a significant decrease in proliferation of CD8+ T cells. Lastly, using flow cytometric analysis we observed a significant increase in expression of CD163, hinting that street RABV is able to polarize macrophages towards a M2-c anti-inflammatory phenotype. Taken together, these results show that street RABV is capable of inducing an anti-inflammatory state in human macrophages, which affects T cell proliferation.Author summaryRabies virus (RABV) is transmitted by a bite or a scratch from an infected animal. Infection leads to a lethal encephalitis and once clinical symptoms occur, there is no effective treatment available. The virus is able to travel from the initial site of infection to the central nervous system without triggering a strong immune response, using multiple mechanisms to evade and suppress the immune system. Up to present it is unclear when and where this immunosuppression is initiated, and if local immune cells are involved as well. Understanding the complete mechanisms of immunosuppression by RABV is essential for the development and improvement of effective post-exposure treatments. In this paper we studied if RABV is able to suppress human primary macrophages as these will be the first antigen-presenting cells that are recruited to the site of infection, and are known to be important in initiating an efficient immune response. We show that RABV is able to bind, but not infect, human macrophages. Binding induces an anti-inflammatory pathway, which leads to limited T cell proliferation and directs macrophages towards and anti-inflammatory state. These results show that RABV-macrophage interactions might indeed be one of the early steps in the onset of RABV-induced immunosuppression.

scholarly journals Street RABV Induces the Cholinergic Anti-inflammatory Pathway in Human Monocyte-Derived Macrophages by Binding to nAChr α7

2021 ◽  
Vol 12 ◽  
Author(s):  
Carmen W. E. Embregts ◽  
Lineke Begeman ◽  
Cees J. Voesenek ◽  
Byron E. E. Martina ◽  
Marion P. G. Koopmans ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Macrophage Polarization ◽  
Flow Cytometric Analysis ◽  
Human Monocyte ◽  
Host Immune System ◽  
Inflammatory Pathway ◽  
Anti Inflammatory ◽  
Alpha Bungarotoxin

Rabies virus (RABV) is able to reach the central nervous system (CNS) without triggering a strong immune response, using multiple mechanisms to evade and suppress the host immune system. After infection via a bite or scratch from a rabid animal, RABV comes into contact with macrophages, which are the first antigen-presenting cells (APCs) that are recruited to the area and play an essential role in the onset of a specific immune response. It is poorly understood how RABV affects macrophages, and if the interaction contributes to the observed immune suppression. This study was undertaken to characterize the interactions between RABV and human monocyte-derived macrophages (MDMs). We showed that street RABV does not replicate in human MDMs. Using a recombinant trimeric RABV glycoprotein (rRABV-tG) we showed binding to the nicotinic acetylcholine receptor alpha 7 (nAChr α7) on MDMs, and confirmed the specificity using the nAChr α7 antagonist alpha-bungarotoxin (α-BTX). We found that this binding induced the cholinergic anti-inflammatory pathway (CAP), characterized by a significant decrease in tumor necrosis factor α (TNF-α) upon LPS challenge. Using confocal microscopy we found that induction of the CAP is associated with significant cytoplasmic retention of nuclear factor κB (NF-κB). Co-cultures of human MDMs exposed to street RABV and autologous T cells further revealed that the observed suppression of MDMs might affect their function as T cell activators as well, as we found a significant decrease in proliferation of CD8+ T cells and an increased production of the anti-inflammatory cytokine IL-10. Lastly, using flow cytometric analysis we observed a significant increase in expression of the M2-c surface marker CD163, hinting that street RABV might be able to affect macrophage polarization. Taken together, these results show that street RABV is capable of inducing an anti-inflammatory state in human macrophages, possibly affecting T cell functioning.

scholarly journals Constitutively Activated DAP12 Induces Functional Anti-Tumor Activation and Maturation of Human Monocyte-Derived DC

2021 ◽  
Vol 22 (3) ◽  
pp. 1241
Author(s):  
Robert Dalton ◽  
Alexandra Calescibetta ◽  
Jun Min Zhou ◽  
Michelle Maurin ◽  
Grace Ward ◽  
...  
Keyword(s):  
Immune Response ◽  
Antigen Presenting Cells ◽  
Human Monocyte ◽  
Tumor Burden ◽  
Strong Immune Response ◽  
Cross Presentation ◽  
Dc Vaccine ◽  
Antigen Presenting ◽  
Constitutively Active

Dendritic cells (DCs) are professional antigen presenting cells with a great capacity for cross-presentation of exogenous antigens from which robust anti-tumor immune responses ensue. However, this function is not always available and requires DCs to first be primed to induce their maturation. In particular, in the field of DC vaccine design, currently available methodologies have been limited in eliciting a sustained anti-tumor immune response. Mechanistically, part of the maturation response is influenced by the presence of stimulatory receptors relying on ITAM-containing activating adaptor molecules like DAP12, that modulates their function. We hypothesize that activating DAP12 in DC could force their maturation and enhance their potential anti-tumor activity for therapeutic intervention. For this purpose, we developed constitutively active DAP12 mutants that can promote activation of monocyte-derived DC. Here we demonstrate its ability to induce the maturation and activation of monocyte-derived DCs which enhances migration, and T cell stimulation in vitro using primary human cells. Moreover, constitutively active DAP12 stimulates a strong immune response in a murine melanoma model leading to a reduction of tumor burden. This provides proof-of-concept for investigating the pre-activation of antigen presenting cells to enhance the effectiveness of anti-tumor immunotherapies.

scholarly journals Regulation of human monocyte HLA-DR and CD4 antigen expression, and antigen presentation by 1,25-dihydroxyvitamin D3

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 189-197 ◽  
Author(s):  
WF Rigby ◽  
M Waugh ◽  
RF Graziano
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Antigen Presentation ◽  
Antigen Expression ◽  
Human Monocyte ◽  
T Cell Proliferation ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Hla Dr ◽  
And Function

Abstract 1,25-Dihydroxyvitamin D3 (1,25(OH)2-D) has been shown to be a macrophage-derived cytokine, capable of regulating myeloid differentiation and T-cell activation in vitro. Therefore, we examined the effects of 1,25(OH)2-D on the monocyte phenotype and function of human peripheral blood monocytes as an index of its biologic role at an inflammatory site. 1,25(OH)2-D treatment consistently and specifically reduced HLA-DR and CD4 expression by monocytes, while CD14 and class I HLA antigen expression were unaffected. Expression of Fc gamma R I-III on monocytes was variably modulated by 1,25(OH)2-D treatment, but no differences in antibody-dependent cell cytotoxicity (ADCC) were observed, measured using either ADCC or anti-Fc gamma R-antibody expressing hybridomas. In contrast, the ability of monocytes to induce antigen-dependent T-cell proliferation was markedly reduced by 1,25(OH)2-D pretreatment for as little as 6 hours. Addition of interleukin-1 (IL-1), IL-6, or indomethacin did not restore antigen- dependent T-cell proliferation, suggesting that this observation was not secondary to changes in IL-1, IL-6, or PGE2 production induced by 1,25(OH)2-D. These data suggest that 1,25(OH)2-D treatment specifically modulates human monocyte phenotype and function, altering HLA-DR antigen expression and antigen presentation, while leaving lytic function intact. These findings may be relevant to the immunobiologic role of 1,25(OH)2-D.

Diminished mitogen-induced T cell proliferation by Trypanosoma cruzi antigens associated with antigen-presenting cell modulation and CD3 signaling

2020 ◽  
Vol 348 ◽  
pp. 103974
Author(s):  
Sergio Gómez-Olarte ◽  
Natalia I. Bolaños ◽  
Adriana Cuéllar ◽  
Concepción J. Puerta ◽  
John M. González
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Trypanosoma Cruzi ◽  
T Cell Proliferation ◽  
Antigen Presenting Cell ◽  
Antigen Presenting

The Hexavalent CD40 Agonist HERA-CD40L Induces T-Cell–mediated Antitumor Immune Response Through Activation of Antigen-presenting Cells

2018 ◽  
Vol 41 (9) ◽  
pp. 385-398 ◽  
Author(s):  
Christian Merz ◽  
Jaromir Sykora ◽  
Viola Marschall ◽  
David M. Richards ◽  
Karl Heinonen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Antigen Presenting Cells ◽  
Antitumor Immune Response ◽  
Antigen Presenting

scholarly journals CD26 Mediates Dissociation of Tollip and IRAK-1 from Caveolin-1 and Induces Upregulation of CD86 on Antigen-Presenting Cells

2005 ◽  
Vol 25 (17) ◽  
pp. 7743-7757 ◽  
Author(s):  
Kei Ohnuma ◽  
Tadanori Yamochi ◽  
Masahiko Uchiyama ◽  
Kunika Nishibashi ◽  
Satoshi Iwata ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Costimulatory Molecule ◽  
Antigen Presenting Cells ◽  
T Cell Proliferation ◽  
Caveolin 1 ◽  
Extracellular Region ◽  
Antigen Presenting

ABSTRACT CD26 is a T-cell costimulatory molecule with dipeptidyl peptidase IV enzyme activity in its extracellular region. We have previously reported that the addition of recombinant soluble CD26 resulted in enhanced proliferation of human T lymphocytes induced by the recall antigen tetanus toxoid (TT) via upregulation of CD86 on monocytes and that caveolin-1 was a binding protein of CD26, and the CD26-caveolin-1 interaction resulted in caveolin-1 phosphorylation (p-cav-1) as well as TT-mediated T-cell proliferation. However, the mechanism involved in this immune enhancement has not yet been elucidated. In the present work, we perform experiments to identify the molecular mechanisms by which p-cav-1 leads directly to the upregulation of CD86. Through proteomic analysis, we identify Tollip (Toll-interacting protein) and IRAK-1 (interleukin-1 receptor-associated serine/threonine kinase 1) as caveolin-1-interacting proteins in monocytes. We also demonstrate that following stimulation by exogenous CD26, Tollip and IRAK-1 dissociate from caveolin-1, and IRAK-1 is then phosphorylated in the cytosol, leading to the upregulation of CD86 via activation of NF-κB. Binding of CD26 to caveolin-1 therefore regulates signaling pathways in antigen-presenting cells to induce antigen-specific T-cell proliferation.

scholarly journals CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.

1995 ◽  
Vol 182 (2) ◽  
pp. 459-465 ◽  
Author(s):  
M F Krummel ◽  
J P Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
Costimulatory Molecule ◽  
Surface Glycoprotein ◽  
T Cell Proliferation ◽  
Cell Surface Glycoprotein ◽  
Costimulatory Signals ◽  
Low Levels ◽  
Opposing Effects ◽  
Antigen Presenting

The importance of the B7/CD28/CTLA-4 molecules has been established in studies of antigen-presenting cell-derived B7 and its interaction with the T cell costimulatory molecule CD28. CTLA-4, a T cell surface glycoprotein that is related to CD28, can also interact with B7-1 and B7-2. However, less is known about the function of CTLA-4, which is expressed at highest levels after activation. We have generated an antibody to CTLA-4 to investigate the consequences of engagement of this molecule in a carefully defined system using highly purified T cells. We show here that the presence of low levels of B7-2 on freshly explanted T cells can partially inhibit T cell proliferation, and this inhibition is mediated by interactions with CTLA-4. Cross-linking of CTLA-4 together with the TCR and CD28 strongly inhibits proliferation and IL-2 secretion by T cells. Finally, results show that CD28 and CTLA-4 deliver opposing signals that appear to be integrated by the T cell in determining the response to activation. These data strongly suggest that the outcome of T cell antigen receptor stimulation is regulated by CD28 costimulatory signals, as well as inhibitory signals derived from CTLA-4.

Sign in / Sign up

Export Citation Format

Share Document