Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2258-2265 ◽  
Author(s):  
Marta Stanzani ◽  
Enrico Orciuolo ◽  
Russell Lewis ◽  
Dimitrios P. Kontoyiannis ◽  
Sergio L. R. Martins ◽  
...  
Keyword(s):  
T Cell ◽  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Cell Function ◽  
T Cell Responses ◽  
Cell Responses ◽  
Cytokine Flow Cytometry ◽  
Induced Apoptosis ◽  
Antigen Presenting

AbstractAspergillus fumigatus (AF) is a ubiquitous mold and is the most common cause of invasive aspergillosis, an important source of morbidity and mortality in immunocompromised hosts. Using cytokine flow cytometry, we assessed the magnitude of functional CD4+ and CD8+ T-cell responses following stimulation with Aspergillus antigens. Relative to those seen with cytomegalovirus (CMV) or superantigen stimulation, responses to Aspergillus antigens were near background levels. Subsequently, we confirmed that gliotoxin, the most abundant mycotoxin produced by AF, was able to suppress functional T-cell responses following CMV or staphylococcal enterotoxin B (SEB) stimulation. Additional studies demonstrated that crude AF filtrates and purified gliotoxin inhibited antigen-presenting cell function and induced the preferential death of monocytes, leading to a marked decrease in the monocyte-lymphocyte ratio. Analysis of caspase-3 activation confirmed that gliotoxin preferentially induced apoptosis of monocytes; similar effects were observed in CD83+ monocyte-derived dendritic cells. Importantly, the physiologic effects of gliotoxin in vitro were observed below concentrations recently observed in the serum of patients with invasive aspergillosis. These studies suggest that the production of gliotoxin by AF may constitute an important immunoevasive mechanism that is mediated by direct effects on antigen-presenting cells and both direct and indirect effects on T cells.

Indirect inhibition of in vivo and in vitro T-cell responses by intravenous immunoglobulins due to impaired antigen presentation

Blood ◽  
2010 ◽  
Vol 115 (9) ◽  
pp. 1727-1734 ◽  
Author(s):  
Éric Aubin ◽  
Réal Lemieux ◽  
Renée Bazin
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
In Vivo Model ◽  
Cell Responses ◽  
Antigen Presenting

Abstract Several clinical studies done with intravenous immunoglobulin (IVIg)–treated autoimmune patients as well as several in vitro studies have revealed that IVIg can reduce polyclonal T-cell activation and modify their cytokine secretion pattern. However, their effect on (auto)antigen-specific T-cell responses has never been addressed directly. In the present work, we used an in vivo model of induction of antigen-specific T-cell responses and an in vitro antigen presentation system to study the effects of IVIg on T-cell responses. The results obtained showed that IVIg inhibited both the in vivo and in vitro antigen-specific T-cell responses but that this effect was the indirect consequence of a reduction in the antigen presentation ability of antigen-presenting cells. The inhibitory effect of IVIg was FcγRIIb-independent, suggesting that IVIg must interfere with activating FcγRs expressed on antigen-presenting cells to reduce their ability to present antigens. Such inhibition of T-cell responses by reducing antigen presentation may therefore contribute to the well-known anti-inflammatory effects of IVIg in autoimmune diseases.

scholarly journals Overactivation of plasmacytoid dendritic cells inhibits antiviral T-cell responses: a model for HIV immunopathogenesis

Blood ◽  
2011 ◽  
Vol 118 (19) ◽  
pp. 5152-5162 ◽  
Author(s):  
Adriano Boasso ◽  
Caroline M. Royle ◽  
Spyridon Doumazos ◽  
Veronica N. Aquino ◽  
Mara Biasin ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Cell Interaction ◽  
Type I ◽  
Cell Responses ◽  
Hiv Exposed ◽  
Antigen Presenting ◽  
Hiv Envelope

AbstractA delicate balance between immunostimulatory and immunosuppressive signals mediated by dendritic cells (DCs) and other antigen-presenting cells (APCs) regulates the strength and efficacy of antiviral T-cell responses. HIV is a potent activator of plasmacytoid DCs (pDCs), and chronic pDC activation by HIV promotes the pathogenesis of AIDS. Cholesterol is pivotal in maintaining HIV envelope integrity and allowing HIV-cell interaction. By depleting envelope-associated cholesterol to different degrees, we generated virions with reduced ability to activate pDCs. We found that APC activation was dissociated from the induction of type I IFN-α/β and indoleamine-2,3-dioxygenase (IDO)–mediated immunosuppression in vitro. Extensive cholesterol withdrawal, resulting in partial protein and RNA loss from the virions, rendered HIV a more powerful recall immunogen for stimulating memory CD8 T-cell responses in HIV-exposed, uninfected individuals. These enhanced responses were dependent on the inability of cholesterol-depleted HIV to induce IFN-α/β.

scholarly journals Design, immunogenicity, and efficacy of a pan-sarbecovirus dendritic-cell targeting vaccine

2021 ◽  
Author(s):  
Séverin Coléon ◽  
Aurélie Wiedemann ◽  
Mathieu Surénaud ◽  
Christine Lacabaratz ◽  
Sophie Hue ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
T Cell Epitopes ◽  
Viral Control ◽  
Cell Responses ◽  
Alignment Analysis ◽  
Antigen Presenting ◽  
New Generation

AbstractThe emergence of SARS-CoV-2 variants of concern (VOCs) that escape pre-existing antibody neutralizing responses increases the need for vaccines that target conserved epitopes and induce cross-reactive B- and T-cell responses. We used a computational approach and sequence alignment analysis to design a new-generation subunit vaccine targeting conserved sarbecovirus B- and T-cell epitopes from Spike (S) and Nucleocapsid (N) to antigen-presenting cells expressing CD40 (CD40.CoV2). We demonstrate the potency of CD40.CoV2 to elicit high levels of cross-neutralizing antibodies against SARS-CoV-2, VOCs, and SARS-CoV-1 in K18-hACE2 transgenic mice, associated with improved viral control and survival after challenge. In addition, we demonstrate the potency of CD40.CoV2 in vitro to recall human multi-epitope, functional, and cytotoxic SARS-CoV-2 S- and N-specific T-cell responses that are unaffected by VOC mutations and cross-reactive with SARS-CoV-1 and, to a lesser extent, MERS epitopes. Overall, these findings provide a framework for a pan-sarbecovirus vaccine.

scholarly journals Glycolysis Inhibition Induces Functional and Metabolic Exhaustion of CD4+ T Cells in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Christina P. Martins ◽  
Lee A. New ◽  
Erin C. O’Connor ◽  
Dana M. Previte ◽  
Kasey R. Cargill ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Function ◽  
T Cell Responses ◽  
Metabolic Reprogramming ◽  
Cell Responses ◽  
T Cell Function

In Type 1 Diabetes (T1D), CD4+ T cells initiate autoimmune attack of pancreatic islet β cells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4+ T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, a competitive inhibitor of the rate limiting glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3 (PFKFB3). Our results confirmed PFK15 inhibited glycolysis utilization by diabetogenic CD4+ T cells and reduced T cell responses to β cell antigen in vitro. In an adoptive transfer model of T1D, PFK15 treatment delayed diabetes onset, with 57% of animals remaining euglycemic at the end of the study period. Protection was due to induction of a hyporesponsive T cell phenotype, characterized by increased and sustained expression of the checkpoint molecules PD-1 and LAG-3 and downstream functional and metabolic exhaustion. Glycolysis inhibition terminally exhausted diabetogenic CD4+ T cells, which was irreversible through restimulation or checkpoint blockade in vitro and in vivo. In sum, our results demonstrate a novel therapeutic strategy to control aberrant T cell responses by exploiting the metabolic reprogramming of these cells during T1D. Moreover, the data presented here highlight a key role for nutrient availability in fueling T cell function and has implications in our understanding of T cell biology in chronic infection, cancer, and autoimmunity.

Antigen-presenting cell function of dendritic cells and macrophages in proliferative T cell responses to soluble and particulate antigens

1986 ◽  
Vol 16 (4) ◽  
pp. 345-350 ◽  
Author(s):  
Martien L. Kapsenberg ◽  
Marcel B. M. Teunissen ◽  
Frank E. M. Stiekema ◽  
Hiskias G. Keizer
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cell Function ◽  
T Cell Responses ◽  
Antigen Presenting Cell ◽  
Cell Responses ◽  
Antigen Presenting

Primary Allogeneic T-Cell Responses Against In Vitro Modified Mantle Cell Lymphoma (MCL) Cells: Implications for Adoptive Immunotherapy after HLA-Matched Stem Cell Transplantation (SCT).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2118-2118
Author(s):  
M. Hoogendoorn ◽  
J. Olde Wolbers ◽  
W. M. Smit ◽  
I. Jedema ◽  
M. R. Schaafsma ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
Cell Responses ◽  
Cell Clones ◽  
Cd40 Activation ◽  
Antigen Presenting

Abstract Allogeneic SCT is being explored as treatment modality for patients with advanced MCL. Complete sustained remissions have been observed after allogeneic SCT illustrating susceptibility of MCL cells to graft-versus-lymphoma (GVL) effect.To potentiate this GVL effect and to reduce graft-versus-host disease (GVHD) reactivity, adoptive transfer of in vitro-selected cytotoxic T cells (CTLs) with specificity for MCL or for hematopoiesis-restricted minor histocompatibility antigens could be an attractive approach. The lack of expression of costimulatory molecules on MCL cells hampers the generation of MCL-reactive T cell-responses. To transform MCL cells into efficient antigen-presenting cells (APCs) we tested the B-lineage specific activating cytokines (IL-4), the unique MCL proliferating cytokine (IL-10) and the ligand of toll like receptor 9, CpG.Furthermore, CD40 triggering using irradiated CD40-L transfected murine fibroblasts (tCD40L) in combination with the cytokines and CpG was examined. The expression of the costimulatory and adhesion molecules CD80, CD86, CD83, CD54 and CD58 of MCL cells of 7 patients, all carrying the t(11;14) translocation, was analyzed by flowcytometry. No upregulation of any of these molecules was observed using the cytokines or CpG. Ligation of CD40 on MCL cells caused a significant upregulation of CD54,CD58, CD80 and CD86 (p<0.01) with maximal expression after 4 days of stimulation. No additional upregulation was induced from IL- 4, IL -10 or CpG. The cumulative production of IL-12 and IL-10 by the MCL cells in response to the various stimuli after 4 days was measured. High amounts of IL-12 (median 1640 pg/mL, range 67–8800 pg/mL) in the absence of IL-10(<100 pg/mL) were synthesized by MCL cells after CD40 activation. Additional stimulation with CpG enhanced the production of IL-12 (1870 pg/mL, range 77–30000 pg/mL) but also the production of IL-10(299 pg/mL, range 0–418 pg/mL). MCL cells were unable to produce IL-12 without CD40 triggering (<5 pg/mL). To analyze the antigen-presenting capacity of primary MCL cells as well as CD40-activated MCL cells (MCL-APC), CD8+ T cells from an unrelated HLA-A and B matched and from a HLA-class I matched donor were stimulated with MCL or MCL-APC cells. Primary MCL cells were not capable of generating T-cell lines. Using a newly developed flowcytometry-based cytotoxicity assay in which the target cells were labeled with CFSE (Jedema,Blood2004;103:2677) we investigate whether the CTL lines, generated against MCL-APC were cytotoxic against MCL-specific targets. The CD8+ CTL lines from both donors effectively killed at an E/T ratio of 10:1 primary MCL (53%) and MCL-APC (83%) and not PHA blasts from the donor. Using limiting dilution assay, in both donor/patient pairs MCL-reactive CTL clones could be generated. 60 out of 89 proliferating CD8+ T cell clones from the first patient/donor pair and 29 out of 74 proliferating CD8+ T cell clones from the second combination showed specific lysis of primary MCL, MCL-APC and PHA blasts from the patient and not of PHA blasts of the donor. Blocking studies using anti-HLA class I antibodies of both CTL lines and clones confirmed class I restricted recognition of the target cells. In conclusion, CD40 activation transforms MCL cells into malignant APC, capable of producing high levels of IL-12 and capable of inducing vigorous MCL-reactive T-cell responses.

scholarly journals Extracellular vesicles in human semen modulate antigen-presenting cell function and decrease downstream antiviral T cell responses

PLoS ONE ◽  
2019 ◽  
Vol 14 (10) ◽  
pp. e0223901 ◽  
Author(s):  
Lucia Vojtech ◽  
Mengying Zhang ◽  
Veronica Davé ◽  
Claire Levy ◽  
Sean M. Hughes ◽  
...  
Keyword(s):  
T Cell ◽  
Extracellular Vesicles ◽  
Cell Function ◽  
T Cell Responses ◽  
Human Semen ◽  
Antigen Presenting Cell ◽  
Cell Responses ◽  
Antigen Presenting
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