Interleukin-15 redirects the outcome of a tolerizing T-cell stimulus from apoptosis to anergy

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1006-1012 ◽  
Author(s):  
Hans Dooms ◽  
Tom Van Belle ◽  
Marjory Desmedt ◽  
Pieter Rottiers ◽  
Johan Grooten
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
T Cell Response ◽  
Peripheral Tolerance ◽  
Clonal Deletion ◽  
Cell Clones ◽  
Receptor Signal ◽  
Cytokine Milieu ◽  
Antigen Presenting

Clonal deletion and anergy are 2 mechanisms used by the immune system to establish peripheral tolerance. In vitro, these mechanisms are induced in T lymphocytes by triggering the T-cell receptor (signal 1) in the absence of costimulation (signal 2). T-cell clones have been shown either to become anergic or to die in response to signal 1 alone; yet the factors that govern this choice remain unknown. This study evaluated the influence of the cytokines interleukin (IL)-2 and IL-15 on the response of the Th1 clone hemagglutinin (T-HA) to signal 1, delivered by stimulation with immobilized anti-CD3 monoclonal antibody (mAb). The response induced by immobilized anti-CD3 mAb was dependent on the cytokine milieu; in the presence of IL-2, T-HA cells were subject to apoptosis, whereas in the presence of IL-15 the cells remained viable but showed proliferative unresponsiveness. After release from the anti-CD3 stimulus, the IL-15-rescued T-HA cells regained responsiveness to IL-2 and IL-15 growth factor activity. However, they were unable to proliferate when stimulated with their cognate antigen presented by professional antigen-presenting cells (signal 1 plus 2) and thus had acquired an anergic phenotype. These data assign a novel function to the previously reported antiapoptotic activity of IL-15, namely, the capacity to redirect the T-cell response to partial stimulation from clonal deletion to anergy. Furthermore, they emphasize that the cytokine environment can critically influence the outcome of a tolerizing stimulus.

Interleukin-15 redirects the outcome of a tolerizing T-cell stimulus from apoptosis to anergy

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1006-1012 ◽  
Author(s):  
Hans Dooms ◽  
Tom Van Belle ◽  
Marjory Desmedt ◽  
Pieter Rottiers ◽  
Johan Grooten
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
T Cell Response ◽  
Peripheral Tolerance ◽  
Clonal Deletion ◽  
Cell Clones ◽  
Receptor Signal ◽  
Cytokine Milieu ◽  
Antigen Presenting

Abstract Clonal deletion and anergy are 2 mechanisms used by the immune system to establish peripheral tolerance. In vitro, these mechanisms are induced in T lymphocytes by triggering the T-cell receptor (signal 1) in the absence of costimulation (signal 2). T-cell clones have been shown either to become anergic or to die in response to signal 1 alone; yet the factors that govern this choice remain unknown. This study evaluated the influence of the cytokines interleukin (IL)-2 and IL-15 on the response of the Th1 clone hemagglutinin (T-HA) to signal 1, delivered by stimulation with immobilized anti-CD3 monoclonal antibody (mAb). The response induced by immobilized anti-CD3 mAb was dependent on the cytokine milieu; in the presence of IL-2, T-HA cells were subject to apoptosis, whereas in the presence of IL-15 the cells remained viable but showed proliferative unresponsiveness. After release from the anti-CD3 stimulus, the IL-15-rescued T-HA cells regained responsiveness to IL-2 and IL-15 growth factor activity. However, they were unable to proliferate when stimulated with their cognate antigen presented by professional antigen-presenting cells (signal 1 plus 2) and thus had acquired an anergic phenotype. These data assign a novel function to the previously reported antiapoptotic activity of IL-15, namely, the capacity to redirect the T-cell response to partial stimulation from clonal deletion to anergy. Furthermore, they emphasize that the cytokine environment can critically influence the outcome of a tolerizing stimulus.

scholarly journals Generation of Cytomegalovirus-Specific Human T-Lymphocyte Clones by Using Autologous B-Lymphoblastoid Cells with Stable Expression of pp65 or IE1 Proteins: a Tool To Study the Fine Specificity of the Antiviral Response

2000 ◽  
Vol 74 (9) ◽  
pp. 3948-3952 ◽  
Author(s):  
Christelle Retière ◽  
Virginie Prod'homme ◽  
Berthe-Marie Imbert-Marcille ◽  
Marc Bonneville ◽  
Henri Vié ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Relevant Information ◽  
In Vitro Models ◽  
T Cell Clones ◽  
Fine Specificity ◽  
Early Protein ◽  
Cell Clones ◽  
Human T Lymphocyte

ABSTRACT Cytotoxic T lymphocytes (CTLs) play a central role in the control of persistent human cytomegalovirus (HCMV) infection in healthy virus carriers. Previous analyses of the specificity of HCMV-reactive CD8+ CTLs drawn from in vitro models in which antigen-presenting cells were autologous fibroblasts infected with laboratory HCMV strains have shown focusing of CTL responses against the major tegument protein, pp65. By contrast, the 72-kDa major immediate-early protein (IE1) was identified as a minor target for this response. Here we have studied the fine specificity and T-cell-receptor features of T-cell clones generated against autologous B lymphoblastoid cell lines stably transfected with HCMV cDNA coding for either pp65 or a natural variant of IE1. This strategy allowed efficient generation of T-cell clones against IE1 and pp65 and led to the identification of several new IE1 and pp65 epitopes, including some located in polymorphic regions of IE1. Such an approach may provide relevant information about the characteristics of the CTL response to IE1 and the effect of viral polymorphism on the immune response against HCMV.

scholarly journals Activation of Hematopoietic Progenitor Kinase 1 Involves Relocation, Autophosphorylation, and Transphosphorylation by Protein Kinase D1

2005 ◽  
Vol 25 (6) ◽  
pp. 2364-2383 ◽  
Author(s):  
Rüdiger Arnold ◽  
Irene M. Patzak ◽  
Brit Neuhaus ◽  
Sadia Vancauwenbergh ◽  
André Veillette ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Hematopoietic Progenitor ◽  
Kinase Activation ◽  
Protein Kinase D1 ◽  
Enzymatic Activation ◽  
Antigen Presenting

ABSTRACT Adaptive immune signaling can be coupled to stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and NF-κB activation by the hematopoietic progenitor kinase 1 (HPK1), a mammalian hematopoiesis-specific Ste20 kinase. To gain insight into the regulation of leukocyte signal transduction, we investigated the molecular details of HPK1 activation. Here we demonstrate the capacity of the Src family kinase Lck and the SLP-76 family adaptor protein Clnk (cytokine-dependent hematopoietic cell linker) to induce HPK1 tyrosine phosphorylation and relocation to the plasma membrane, which in lymphocytes results in recruitment of HPK1 to the contact site of antigen-presenting cell (APC)-T-cell conjugates. Relocation and clustering of HPK1 cause its enzymatic activation, which is accompanied by phosphorylation of regulatory sites in the HPK1 kinase activation loop. We show that full activation of HPK1 is dependent on autophosphorylation of threonine 165 and phosphorylation of serine 171, which is a target site for protein kinase D (PKD) in vitro. Upon T-cell receptor stimulation, PKD robustly augments HPK1 kinase activity in Jurkat T cells and enhances HPK1-driven SAPK/JNK and NF-κB activation; conversely, antisense down-regulation of PKD results in reduced HPK1 activity. Thus, activation of major lymphocyte signaling pathways via HPK1 involves (i) relocation, (ii) autophosphorylation, and (iii) transphosphorylation of HPK1 by PKD.

scholarly journals Development of Stable Chimeric IL-15 for Trans-Presentation by the Antigen Presenting Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Manoj Patidar ◽  
Naveen Yadav ◽  
Sarat K. Dalai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Half Life ◽  
Therapeutic Potential ◽  
Chimeric Protein ◽  
Antigen Presenting Cells ◽  
T Cell Response ◽  
Antigen Presenting

IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15Rβ. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8+ T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8+ T cell responses.

scholarly journals Characterization of the T-Cell Receptor Vβ Repertoire in the Human Immune Response against Leishmania Parasites

2006 ◽  
Vol 74 (8) ◽  
pp. 4757-4765 ◽  
Author(s):  
Jorge Clarêncio ◽  
Camila I. de Oliveira ◽  
Glória Bomfim ◽  
Margarida M. Pompeu ◽  
Maria Jania Teixeira ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cell Receptor ◽  
Peripheral Blood Mononuclear ◽  
Cell Clones ◽  
Human Immune Response ◽  
Lymph Node Cells

ABSTRACT In order to explore a possible presence of hyperreactive T-cell clones in human cutaneous leishmaniasis (CL), we have investigated, by flow cytometry, the expression of Vβ chains of T-cell receptors (TCRs) in the following types of cells: (i) peripheral blood mononuclear cells (PBMCs) from CL patients, which were then compared to those from normal volunteers; (ii) unstimulated and soluble Leishmania antigen-stimulated draining lymph node cells from CL patients; (iii) PBMCs from volunteers before versus after Leishmania immunization; and (iv) PBMCs from healthy volunteers that were primed in vitro with live Leishmania parasites. Our results show a modulation in the TCR Vβ repertoire during CL and after antigen stimulation of patients' cells. Vaccination, however, leads to a broad expansion of different Vβ TCRs. We also observed an association between TCR Vβ12 expression, T-cell activation, and gamma interferon production upon in vitro priming with Leishmania. Collectively, these results both indicate that infection with live parasites or exposure to parasite antigen can modulate the TCR Vβ repertoire and suggest that TCR Vβ12 may be implicated in the response to Leishmania.

Live attenuated oral Salmonella platform for effective T- and B-cell targeting of PD-L1.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 74-74
Author(s):  
Sébastien Wieckowski ◽  
Heiko Smetak ◽  
Iris Kobl ◽  
Lilli Podola ◽  
Anne-Lucie Nugues ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Immunity ◽  
Cell Response ◽  
Regulatory Protein ◽  
T Cell Response ◽  
Eukaryotic Expression ◽  
Peripheral Tolerance ◽  
Tumor Associated Antigens ◽  
T Cell Vaccination

74 Background: Significant progresses have been recently achieved in cancer vaccines, yet novel immunization solutions to deliver efficiently tumor-associated antigens to professional antigen-presenting cells, and to overcome the peripheral tolerance and the immunosuppressive tumor microenvironment that prevent the eradication of cancer in most of patients, are urgently needed. VAXIMM is developing a unique and versatile oral T-cell vaccination platform based on the FDA-approved live-attenuated Salmonella Typhi strain Ty21a vaccine Vivotif, capable of delivering tumor-associated antigens encoded in DNA expression construct to the gut-associated lymphoid tissue, breaking immune tolerance and inducing effective anti-tumor immunity. Methods: This study summarizes the immunogenicity and antileukemia efficacy of VXM10 vaccines based on the live-attenuated Salmonella Typhimurium strain SL7207, transformed with a eukaryotic expression plasmid encoding different variants of the murine PD-L1 protein. Results: The antileukemia activity of VXM10 was evaluated in the FBL-3 disseminated model of leukemia, in which the tumor cells strongly express PD-L1. Multiple oral administrations of VXM10 vaccines produced a strong anti-tumor effect, with 100% of surviving animals 80 days after challenge with FBL3 leukemia in the highest dose groups. Moreover, 100% of long-term surviving mice resisted re-challenge with FBL-3 cells, demonstrating that vaccination with VXM10 generated a potent memory T cell response against the leukemia. Importantly, full leukemia control was achieved in both prophylactic and therapeutic settings. Upon immunization with VXM10 vaccines, T cell response was raised against PD-L1 epitopes after in vitro restimulation of the splenocytes, and anti-PD-L1 antibodies were detected in the serum. The precise mechanism of action of VXM10 vaccines is currently being investigated. Conclusions: This study provides further evidence that VAXIMM’s oral T-cell vaccination platform can be employed to stimulate anti-tumor immunity against antigens of the immune checkpoint regulatory protein PD-L1. These data paved the way for advancing the development of VXM10 into clinical development.

scholarly journals In vitro correlate for a clonal deletion mechanism of immune response gene-controlled nonresponsiveness.

1983 ◽  
Vol 157 (3) ◽  
pp. 998-1005 ◽  
Author(s):  
N Ishii ◽  
Z A Nagy ◽  
J Klein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Response Gene ◽  
Mouse Strains ◽  
Single Chain ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Class Ii Mhc ◽  
Antigen Presenting

We used T cell-antigen-presenting cell (APC) combinations from two pairs of recombinant mouse strains, B10.A(4R)-B10.A(2R) and B10.S(7R)-B10.S(9R) (abbreviated 4R, 2R, 7R, 9R, respectively), which differ from each other only in the nonexpression vs. expression of cell-surface E molecules, to study the mechanism of the Ir gene-controlled (E-restricted) response to the terpolymer poly(glu51lys34tyr15) (GLT). No response to GLT occurred when the APC were from E-nonexpressor strains 4R and 7R. When APC from E-expressor strains were used and alloreactivity against the incompatible E molecules was removed by BUdR + light treatment, 7R T cells responded to GLT presented by 9R APC, but 4R T cells failed to respond to GLT presented by 2R APC. However, 4R T cells mounted a proliferative response to GLT presented by fully allogeneic 5R or 9R APC. The latter response was completely abolished by the depletion of cells alloreactive against 2R and 5R or 2R and 9R. Since removal of alloreactivity against 5R plus 9R did not affect the response of 4R T cells to GLT presented by either 5R or 9R cells, we conclude that the 4R T cells generated in response to GLT cross-react with the additional incompatibility presented by 2R cells, that is, the Ek beta chain. In contrast, 7R T cells recognizing GLT presented by 9R APC do not cross-react with Ek beta. These results demonstrate that "blind spots" in the T cell repertoire produced by depletion of cells alloreactive against a single chain of a class II MHC molecule can render a strain nonresponsive to a synthetic polypeptide antigen, and that this nonresponsiveness corresponds to that attributed to the MHC-linked Ir genes.

scholarly journals Identification and tracking of alloreactive T cell clones in Rhesus Macaques through the RM-scTCR-Seq platform.

2021 ◽  
Author(s):  
Ulrike Gerdemann ◽  
Ryan A. Fleming ◽  
James Kaminski ◽  
Connor McGuckin ◽  
Xianliang Rui ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Single Cells ◽  
Cell Receptor ◽  
Cytotoxic T Cell ◽  
Cell Clones ◽  
Alloreactive T Cell

T cell receptor clonotype tracking is a powerful tool for interrogating T cell mediated immune processes. New methods to pair a single cells transcriptional program with its T cell receptor (TCR) identity allow monitoring of T cell clonotype-specific transcriptional dynamics. While these technologies have been available for human and mouse T cells studies, they have not been developed for Rhesus Macaques, a critical translational organism for autoimmune diseases, vaccine development and transplantation. We describe a new pipeline, RM-scTCR-Seq, which, for the first time, enables RM specific single cell TCR amplification, reconstitution and pairing of RM TCRs with their transcriptional profiles. We apply this method to a RM model of GVHD, and identify and track in vitro detected alloreactive clonotypes in GVHD target organs and explore their GVHD driven cytotoxic T cell signature. This novel, state-of-the-art platform fundamentally advances the utility of RM to study protective and pathogenic T cell responses.

scholarly journals Primer on the Pathogenesis of Severe COVID-19: Part One

2020 ◽  
Author(s):  
Thomas Walsh
Keyword(s):  
T Cell ◽  
Severe Acute Respiratory Syndrome ◽  
Membrane Vesicles ◽  
Cell Receptor ◽  
T Cell Response ◽  
Interferon Response ◽  
Protein Kinase R ◽  
Unfolded Protein ◽  
Cytokine Milieu ◽  
The Unfolded Protein Response

In Part One of this exploration of the pathogenesis of coronavirus disease (COVID-19), the author will evaluate the viral and cellular immunological basis for the condition. The virus demonstrates a remarkable capability not just to evade, but to exploit host immune characteristics to perpetuate viral replication. In this regard, severe acute respiratory syndrome (SARS)/severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disables most antiviral mechanisms, including the early interferon response, and avoids detection to permit unimpeded viral multiplication. Consequently, antigen-presenting cells fail to adequately stimulate the T-cell receptor. As a consequence, T-cell p53 remains highly expressed, which in turn disables an adequate effector T-cell response. Replicating SARS-CoV-2 double-strand RNA robustly activates protein kinase R (PKR)/PKR-like endoplasmic reticulum kinase (PERK). While the virus is grossly invulnerable to its antiviral effects, PKR is crucial for effecting the cytokine milieu in COVID-19. PERK is a component of the unfolded protein response, which eventuates in autophagy. SARS virions use double-membrane vesicles and adapt PERK signalling not only to avoid autophagy, but to facilitate replication. Viral activation of PKR/PERK is mutually exclusive to NLRP3 stimulation. The NLRP3 pathway elaborates IL-1β. This is chiefly a feature of paediatric SARS/SARS-CoV-2 cases. The difficulties encountered in predicting outcome and forging effective therapeutics speaks to the breadth of complexity of the immunopathogenesis of this virus.

Regulation of alveolar macrophage-T cell interactions during Th1-type sarcoid inflammatory process

1999 ◽  
Vol 277 (2) ◽  
pp. L240-L250 ◽  
Author(s):  
Carlo Agostini ◽  
Livio Trentin ◽  
Alessandra Perin ◽  
Monica Facco ◽  
Marta Siviero ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Costimulatory Molecules ◽  
T Cell Response ◽  
Accessory Function ◽  
B7 Family ◽  
Ifn Γ ◽  
Low Levels ◽  
Antigen Presenting

The accessory function of antigen-presenting cells depends on the presence of a number of costimulatory molecules, including members of the B7 family (CD80 and CD86) and the CD5 coligand CD72. The aim of this study was to evaluate the regulation of T cell-antigen-presenting cell costimulatory pathways in the lung of patients with a typical Th1-type reaction, i.e., sarcoidosis. Although normal alveolar macrophages (AMs) did not bear or bore low levels of costimulatory molecules, AMs from sarcoid patients with CD4 T-cell alveolitis upmodulated CD80, CD86, and CD72 and expressed high levels of interleukin (IL)-15; lymphocytes accounting for T-cell alveolitis expressed Th1-type cytokines [interferon (IFN)-γ and/or IL-2] and bore high levels of CD5 and CD28 but not of CD152 molecules. In vitro stimulation of AMs with Th1-related cytokines (IL-15 and IFN-γ) upregulated the expression of CD80 and CD86 molecules. However, stimulation with IL-15 induced the expression of Th1-type cytokines (IFN-γ) and CD28 on sarcoid T cells, suggesting a role for this macrophage-derived cytokine in the activation of the sarcoid T-cell pool. The hypothesis that CD80 and CD86 molecules regulate the sarcoid T-cell response was confirmed by the evidence that AMs induced a strong proliferation of T cells that was inhibited by pretreatment with CD80 and CD86 monoclonal antibodies. To account for these data, it is proposed that locally released cytokines provide AMs with accessory properties that contribute to the development of sarcoid T-cell alveolitis.

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