scholarly journals Mechanical feedback enables catch bonds to selectively stabilize scanning microvilli at T-cell surfaces

2019 ◽  
Author(s):  
Robert H. Pullen ◽  
Steven M. Abel
Keyword(s):  
T Cells ◽  
Single Molecule ◽  
Physical Mechanism ◽  
Dependent Manner ◽  
Receptor Ligand ◽  
Active Motion ◽  
Bond Behavior ◽  
Applied Forces ◽  
Antigen Presenting ◽  
Catch Bonds

AbstractT cells use microvilli to search the surfaces of antigen-presenting cells for antigenic ligands. The active motion of scanning microvilli provides a force-generating mechanism that is intriguing in light of single-molecule experiments showing that applied forces on stimulatory receptor-ligand bonds increase their lifetimes (catch-bond behavior). In this work, we introduce a theoretical framework to explore the motion of a microvillus tip above an antigen-presenting surface when receptors on the tip stochastically bind to ligands on the surface and dissociate from them in a force-dependent manner. Forces on receptor-ligand bonds impact the motion of the microvillus, leading to feedback between binding and microvillar motion. We use computer simulations to show that the average microvillus velocity varies in a ligand-dependent manner, that catch bonds generate responses in which some microvilli almost completely stop while others move with a broad distribution of velocities, and that the frequency of stopping depends on the concentration of stimulatory ligands. Typically, a small number of catch bonds initially immobilize the microvillus, after which additional bonds accumulate and increase the cumulative receptor-engagement time. Our results demonstrate that catch bonds can selectively slow and stabilize scanning microvilli, suggesting a physical mechanism that may contribute to antigen discrimination by T cells.

scholarly journals Mechanical feedback enables catch bonds to selectively stabilize scanning microvilli at T-cell surfaces

2019 ◽  
Vol 30 (16) ◽  
pp. 2087-2095 ◽  
Author(s):  
Robert H. Pullen ◽  
Steven M. Abel
Keyword(s):  
T Cells ◽  
Single Molecule ◽  
Physical Mechanism ◽  
Dependent Manner ◽  
Receptor Ligand ◽  
Active Motion ◽  
Bond Behavior ◽  
Applied Forces ◽  
Antigen Presenting ◽  
Catch Bonds

T-cells use microvilli to search the surfaces of antigen-presenting cells for antigenic ligands. The active motion of scanning microvilli provides a force-generating mechanism that is intriguing in light of single-molecule experiments showing that applied forces increase the lifetimes of stimulatory receptor–ligand bonds (catch-bond behavior). In this work, we introduce a theoretical framework to explore the motion of a microvillar tip above an antigen-presenting surface when receptors on the tip stochastically bind to ligands on the surface and dissociate from them in a force-dependent manner. Forces on receptor-ligand bonds impact the motion of the microvillus, leading to feedback between binding and microvillar motion. We use computer simulations to show that the average microvillar velocity varies in a ligand-dependent manner; that catch bonds generate responses in which some microvilli almost completely stop, while others move with a broad distribution of velocities; and that the frequency of stopping depends on the concentration of stimulatory ligands. Typically, a small number of catch bonds initially immobilize the microvillus, after which additional bonds accumulate and increase the cumulative receptor-engagement time. Our results demonstrate that catch bonds can selectively slow and stabilize scanning microvilli, suggesting a physical mechanism that may contribute to antigen discrimination by T-cells.

Interferon-γ-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2570-2577 ◽  
Author(s):  
John Stagg ◽  
Sandra Pommey ◽  
Nicoletta Eliopoulos ◽  
Jacques Galipeau
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Stromal Cells ◽  
Matrix Protein ◽  
Marrow Stromal Cells ◽  
Human Mscs ◽  
Dependent Manner ◽  
Antigen Presenting ◽  
Significant Production

AbstractSeveral studies have demonstrated that marrow stromal cells (MSCs) can suppress allogeneic T-cell responses. However, the effect of MSCs on syngeneic immune responses has been largely overlooked. We describe here that primary MSCs derived from C57BL/6 mice behave as conditional antigen-presenting cells (APCs) and can induce antigen-specific protective immunity. Interferon gamma (IFNγ)-treated C57BL/6 MSCs, but not unstimulated MSCs, cocultured with ovalbumin-specific major histocompatibility (MHC) class II-restricted hybridomas in the presence of soluble ovalbumin-induced significant production of interleukin-2 (IL-2) in an antigen dose-dependent manner (P < .005). IFNγ-treated MSCs could further activate in vitro ovalbumin-specific primary transgenic CD4+ T cells. C57BL/6 MSCs, however, were unable to induce antigen cross-presentation via the MHC class I pathway. When syngeneic mice were immunized intraperitoneally with ovalbumin-pulsed IFNγ-treated MSCs, they developed antigen-specific cytotoxic CD8+ T cells and became fully protected (10 of 10 mice) against ovalbumin-expressing E.G7 tumors. Human MSCs were also studied for antigen-presenting functions. IFNγ-treated DR1-positive human MSCs, but not unstimulated human MSCs, induced significant production of IL-2 when cocultured with DR1-restricted influenza-specific humanized T-cell hybridomas in the presence of purified influenza matrix protein 1. Taken together, our data strongly suggest that MSCs behave as conditional APCs in syngeneic immune responses. (Blood. 2006;107:2570-2577)

scholarly journals Selective tumor antigen vaccine delivery to human CD169+antigen-presenting cells using ganglioside-liposomes

2020 ◽  
Vol 117 (44) ◽  
pp. 27528-27539
Author(s):  
Alsya J. Affandi ◽  
Joanna Grabowska ◽  
Katarzyna Olesek ◽  
Miguel Lopez Venegas ◽  
Arnaud Barbaria ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Ex Vivo ◽  
Antigen Presenting Cells ◽  
Dependent Manner ◽  
Cross Presentation ◽  
Vaccine Carrier ◽  
Antigen Presenting

Priming of CD8+T cells by dendritic cells (DCs) is crucial for the generation of effective antitumor immune responses. Here, we describe a liposomal vaccine carrier that delivers tumor antigens to human CD169/Siglec-1+antigen-presenting cells using gangliosides as targeting ligands. Ganglioside-liposomes specifically bound to CD169 and were internalized by in vitro-generated monocyte-derived DCs (moDCs) and macrophages and by ex vivo-isolated splenic macrophages in a CD169-dependent manner. In blood, high-dimensional reduction analysis revealed that ganglioside-liposomes specifically targeted CD14+CD169+monocytes and Axl+CD169+DCs. Liposomal codelivery of tumor antigen and Toll-like receptor ligand to CD169+moDCs and Axl+CD169+DCs led to cytokine production and robust cross-presentation and activation of tumor antigen-specific CD8+T cells. Finally, Axl+CD169+DCs were present in cancer patients and efficiently captured ganglioside-liposomes. Our findings demonstrate a nanovaccine platform targeting CD169+DCs to drive antitumor T cell responses.

Human mucosal-associated invariant T cells respond to Mucorales species in a MR1-dependent manner

2020 ◽  
Author(s):  
Sarah Böttcher ◽  
Susann Hartung ◽  
Florian Meyer ◽  
Silke Rummler ◽  
Kerstin Voigt ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Activation ◽  
Cell Receptor ◽  
Mucor Circinelloides ◽  
Dependent Manner ◽  
Rhizopus Microsporus ◽  
Mait Cells ◽  
Cd107a Expression ◽  
Invariant T Cells ◽  
Antigen Presenting

Abstract Activation of mucosal-associated invariant T cells (MAIT cells) by certain bacteria, viruses, and yeast is well studied, but the activation potential of filamentous moulds from the order Mucorales is not known. Here, we show a rapid response of human MAIT cells against the Mucorales species Mucor circinelloides, Rhizopus arrhizus, and Rhizopus microsporus. This activation included upregulation of CD69 and degranulation marked by increased CD107a expression, while intracellular perforin and granzyme A expression were reduced. Furthermore, blocking of the antigen-presenting molecule major histocompatibility complex class I-related abrogated MAIT cell activation demonstrating a T cell receptor-dependent stimulation by Mucorales.

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.

scholarly journals Early T cell receptor signals globally modulate ligand:receptor affinities during antigen discrimination

2017 ◽  
Vol 114 (46) ◽  
pp. 12190-12195 ◽  
Author(s):  
Rafal M. Pielak ◽  
Geoff P. O’Donoghue ◽  
Jenny J. Lin ◽  
Katherine N. Alfieri ◽  
Nicole C. Fay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Single Molecule ◽  
Cell Activation ◽  
Cell Receptor ◽  
Physical Constraints ◽  
Molecular Binding ◽  
Antigen Presenting

Antigen discrimination by T cells occurs at the junction between a T cell and an antigen-presenting cell. Juxtacrine binding between numerous adhesion, signaling, and costimulatory molecules defines both the topographical and lateral geometry of this cell–cell interface, within which T cell receptor (TCR) and peptide major histocompatibility complex (pMHC) interact. These physical constraints on receptor and ligand movement have significant potential to modulate their molecular binding properties. Here, we monitor individual ligand:receptor binding and unbinding events in space and time by single-molecule imaging in live primary T cells for a range of different pMHC ligands and surface densities. Direct observations of pMHC:TCR and CD80:CD28 binding events reveal that the in situ affinity of both pMHC and CD80 ligands for their respective receptors is modulated by the steady-state number of agonist pMHC:TCR interactions experienced by the cell. By resolving every single pMHC:TCR interaction it is evident that this cooperativity is accomplished by increasing the kinetic on-rate without altering the off-rate and has a component that is not spatially localized. Furthermore, positive cooperativity is observed under conditions where the T cell activation probability is low. This TCR-mediated feedback is a global effect on the intercellular junction. It is triggered by the first few individual pMHC:TCR binding events and effectively increases the efficiency of TCR scanning for antigen before the T cell is committed to activation.

Immunomodulatory Effects of STI571 in Chronic Myeloid Leukaemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2198-2198
Author(s):  
Dagmar Bund ◽  
Ting Yang ◽  
Raymund Buhmann ◽  
Hans-Jochem Kolb
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cellular Immune Response ◽  
Myeloid Cells ◽  
Dependent Manner ◽  
Activation Markers ◽  
Cellular Immune ◽  
Antigen Presenting

Abstract Background: The tyrosine kinase inhibitor imatinib (imatinib, STI571, Glivec, and Gleevec) is highly effective in the treatment of chronic myeloid leukaemia (CML) and has already been shown to be effective in the setting of allogeneic stem cell transplantation. But until now, less is known with respect to its immunomodulating effects. Objective: In the present survey we investigated, whether imatinib could modify the antigen-presenting capacity of myeloid cells and in turn affects the cellular immune response. Method: For this purpose, patient derived chronic myeloid cells were incubated with different concentrations of imatinib (0, 1, 2, or 5microM), characterized for their antigen-presenting profile and their stimulatory capacity in the context of HLA-matched and mismatched T-cells. After 5 days, the proliferative immune response was evaluated in presence or absence of different concentrations of imatinib and altered effector-to-target ratios. Thereby, proliferation was detected via a CFDA, SE (5,6-carboxyfluorescein diacetate succinimidyl ester) based assay. Result: The proliferative capacity of the T- cells (allogeneic, HLA-mismatched) was inhibited by imatinib in a dose-dependent manner. Also, the expression of the activation markers was reduced in the presence of the different STI571 concentrations. Moreover, myeloid blasts were sensitized for T cell mediated effector functions by pre-treatment with increasing concentrations of imatinib. Conclusion: Taken together, imatinib can interfere with the T cellular immune response in vitro, and its impact on graft-versus-leukemia (GvL) and graft-versus-host (GvH) reactions will be further investigated.

Efficient Binding, but Moderate Modulation, of Human Dendritic Cell Functions by Milatuzumab, a Humanized Anti-CD74 Monoclonal Antibody

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2649-2649 ◽  
Author(s):  
Xiaochuan Chen ◽  
Chien-Hsing Chang ◽  
David Goldenberg
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Cell Viability ◽  
Antigen Presenting Cells ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Immune Functions ◽  
Cell Functions ◽  
Antigen Presenting

Abstract Milatuzumab (hLL1, Immunomedics, Inc.), a humanized anti-CD74 immunoglobulin-G monoclonal antibody (MAb), has been shown to have therapeutic activity against CD74-expressing B-cell malignancies in vitro and in xenografts models, and is in clinical evaluation as a therapeutic MAb for non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma. Since it is unclear whether this MAb has any effects on human antigen-presenting cells that express CD74, we investigated the binding efficiency, viability, and functional modulation of human dendritic cells (DC), the professional and most potent antigen-presenting cells, exposed to milatuzumab. We found that milatuzumab bound efficiently with B cells, monocytes, and different subsets of blood DCs including myeloid DC1 (BDCA-1+), myeloid DC2 (BDCA-3+) and plasmacytoid DC (BDCA-2+) in human PBMC, as well as with monocyte-derived immature DCs, but not LPS-matured DCs. The side-by-side comparative cytotoxicity assay showed that milatuzumab, in the presence of a second antibody for cross-linking (GAH, the F(ab′)2 of goat anti-human IgG Fcgamma-specific), dramatically reduced the cell viability of Daudi B-lymphoma cells, but did not influence the cell viability or induce apoptosis in monocyte-derived DCs, even at high concentations up to 50 μg/ml. At the concentrations ranging from 0.05 to 5 μg/ml, milatuzumab upregulated the expression of the antigen-presenting molecule, HLA-DR, and costimulatory molecules, CD54 and CD86, in human monocyte-derived DCs in a moderate, but dose-dependent manner, suggesting that milatuzumab could enhance DC constitutive maturation. Although this effect was not reflected by an enhanced T-cell expansion, as shown by unaltered CFSE-low, -medium, and –high peaks in total and CD4+ and CD4− T cells, milatuzumab-treated DCs could moderately promote the differentiation of CD4+ naïve T cells toward more Th1 effector cells, suggesting that milatuzumab can modulate DC functions, inducing the polarization and differentiation of functional Th cells. These data highlight the prospects of milatuzumab as a novel immunotherapeutic agent that possesses not only direct anti-proliferative effects against CD74+ hematological malignancies, but also some regulatory effects on DC-mediated immune functions, and no cytotoxic effect on DCs.

C-Type Lectin Receptor Mediated Immune Recognition of ADAMTS13 Promotes HLA-DRB1*11 Dependent Presentation of CUB1-2 Derived Peptides by Dendritic Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 196-196
Author(s):  
Nicoletta Sorvillo ◽  
Simon D van Haren ◽  
Wouter Pos ◽  
Eszter Herczenik ◽  
Rob Fijnheer ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Class Ii ◽  
Immune Recognition ◽  
Dependent Manner ◽  
Sirna Silencing ◽  
Antigen Presenting

Abstract Abstract 196 ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation by virtue of its ability to process newly released ultra-large von Willebrand factor (VWF) multimers on the surface of endothelial cells. Autoantibodies directed against ADAMTS13 prohibit the processing of VWF multimers initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). HLA-DRB1*11 has recently been identified as a risk factor for acquired TTP. This finding implies that formation of autoantibodies towards ADAMTS13 depends on appropriate presentation of ADAMTS13 derived peptides to CD4+ T-cells by antigen presenting cells. Here, we investigate endocytosis of recombinant ADAMTS13 by immature monocyte-derived dendritic cells (iDCs) using flow cytometry and confocal microscopy. Upon incubation of fluorescently labeled-rADAMTS13 with DCs, a time- and concentration dependent uptake of ADAMTS13 was observed. Endocytosis of ADAMTS13 was completely blocked upon addition of EGTA and mannan. We subsequently explored involvement of C-type lectins (CLRs) in the uptake of ADAMTS13 using specific blocking antibodies and siRNA silencing. We found that ADAMTS13 endocytosis was significantly decreased in cells treated with a monoclonal antibody directed towards macrophage mannose receptor (MR). Furthermore siRNA silencing of MR reduced the uptake of ADAMTS13 by dendritic cells. In vitro binding studies revealed that ADAMTS13 interacts with the carbohydrate recognition domains of MR. These data show that ADAMTS13 is internalized by iDCs in a MR-dependent manner. Antigen presenting cells continuously process endogenous and exogenous antigens into small peptides that are loaded on MHC class I or MHC class II for presentation to T lymphocytes. We have recently developed a method to analyze HLA-DR-presented peptide repertoires of dendritic cells pulsed with antigen (van Haren et al., 2011). Here, we addressed which ADAMTS13-derived peptides were presented on MHC class II alleles of a panel of both HLA-DRB1*11 positive and negative donors. Compared to previous studies with model antigens only a limited number of ADAMTS13-derived peptides were presented on MHC class II. Inspection of peptide-profiles obtained from DRB1*11 positive individuals revealed that two antigenic “core” peptides derived from the CUB1-2 domains of ADAMTS13 were presented by a DR11-positive donor. In addition to these immuno-dominant peptides several other peptides were also presented although with a markedly reduced efficiency. Our findings show that DRB1*11 expressing antigen presenting cells preferentially present antigenic “core” peptides derived from the CUB1-2 domains of ADAMTS13. We hypothesize that functional presentation of these peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low affinity self-reactive CD4+ T cells that have escaped negative selection in the thymus. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Capsaicin activates TRPV1 in human Langerhans cells and inhibits mucosal HIV-1 transmission via secreted CGRP

2021 ◽  
Author(s):  
Emmanuel Cohen ◽  
Aiwei Zhu ◽  
Cédric Auffray ◽  
Morgane Bomsel ◽  
Yonatan Ganor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ion Channel ◽  
Cd4 T Cells ◽  
Langerhans Cells ◽  
Dependent Manner ◽  
Mucosal Transmission ◽  
Trans Infection ◽  
Antigen Presenting ◽  
Hiv 1

AbstractUpon its mucosal transmission, human immunodeficiency virus type 1 (HIV-1) rapidly targets resident antigen-presenting Langerhans cells (LCs) in genital epithelia, which subsequently trans-infect CD4+ T-cells. We previously described an inhibitory neuro-immune sensory mucosal crosstalk, whereby peripheral pain-sensing nociceptor neurons, innervating all mucosal epithelia and associating with LCs, secret the neuropeptide calcitonin gene-related peptide (CGRP) that strongly inhibits HIV-1 trans-infection. Moreover, we reported that LCs secret low levels of CGRP that are further increased by CGRP itself via an autocrine/paracrine mechanism. As nociceptors secret CGRP following activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), we investigated whether LCs also express functional TRPV1. We found that human LCs expressed TRPV1 mRNA and protein. TRPV1 in LCs was functional, as the TRPV1 agonists capsaicin (CP) and resiniferatoxin (RTX) induced Ca2+ influx in a dose-dependent manner. Treatment of LCs with CP and the TRPV1 agonist rutaecarpine (Rut) increased CGRP secretion, reaching concentrations close to its IC50 for inhibition of HIV-1 trans-infection. Accordingly, CP significantly inhibited HIV-1 trans-infection, which was abrogated by antagonists of both TRPV1 and the CGRP receptor. Finally, pre-treatment of inner foreskin tissue explants with CP markedly increased CGRP secretion, and upon subsequent polarized exposure to HIV-1, inhibited increase in LC-T-cell conjugate formation and T-cell infection. Together, our results reveal that alike nociceptors, LCs express functional TRPV1, whose activation induces CGRP secretion that inhibits mucosal HIV-1 transmission. Our studies could permit re-positioning of formulations containing TRPV1 agonists, already approved for pain relief, as novel topical microbicides against HIV-1.Significance StatementUpon its sexual transmission, HIV-1 targets different types of mucosal immune cells, such as antigen-presenting Langerhans cells (LCs). In turn, LCs transfer HIV-1 to its principal cellular targets, namely CD4+ T-cells, in a process termed trans-infection. We previously discovered that the mucosal neuropeptide CGRP strongly inhibits trans-infection. CGRP is principally secreted from pain-sensing peripheral neurons termed nociceptors, once activated via their TRPV1 ion channel. Herein, we reveal that LCs also express functional TRPV1, whose activation induces secretion of CGRP that inhibits mucosal HIV-1 transmission. Accordingly, molecules activating TRPV1 and inducing CGRP secretion could be used to prevent mucosal HIV-1 transmission. This approach represents an original neuro-immune strategy to fight HIV-1.

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