scholarly journals Escherichia coli Prevents Phagocytosis-Induced Death of Macrophages via Classical NF-κB Signaling, a Link to T-Cell Activation

2006 ◽  
Vol 74 (10) ◽  
pp. 5989-6000 ◽  
Author(s):  
Heinrich V. Groesdonk ◽  
Silke Schlottmann ◽  
Friederike Richter ◽  
Michael Georgieff ◽  
Uwe Senftleben
Keyword(s):  
Escherichia Coli ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Adaptive Immune Response ◽  
Laboratory Strain ◽  
Pyrrolidine Dithiocarbamate ◽  
E Coli ◽  
Adaptive Immune

ABSTRACT NF-κB is a crucial mediator of macrophage inflammatory responses, but its role in the context of pathogen-induced adaptive immune responses has yet to be elucidated. Here, we demonstrate that classical NF-κB activation delays phagocytosis-induced cell death (PICD) in Raw 264.7 and bone marrow-derived macrophages (BMDMs) upon ingestion of bacteria from the Escherichia coli laboratory strain Top10. By expression of a nondegradable form of IκBα (superrepressor) and pyrrolidine dithiocarbamate treatment, prolonged activation of NF-κB upon bacterial coculture is suppressed, whereas initial induction is only partially inhibited. This activation pattern results in partial inhibition of cellular activation and reduced expression of costimulatory CD86. Notably, suppression of classical NF-κB activation does not influence bacterial uptake rates but is followed by increased production of oxygen radicals and enhanced intracellular killing in Raw macrophages. This is associated with reduced expression of NF-κB-dependent antiapoptotic c-IAP-2 and a loss of the mitochondrial transmembrane potential. Accordingly, NF-κB inhibition in Raw cells and BMDMs causes increased apoptotic rates within 12 h of bacterial ingestion. Interestingly, accelerated eradication of E. coli in NF-κB-inhibited macrophages is associated with reduced antigen-specific T-cell activation in macrophage-lymphocyte cocultures. These data suggest that E. coli inhibits PICD of macrophages via classical, antiapoptotic NF-κB activation and thus facilitates signaling to T cells. Subsequently, a proper adaptive immune response is likely to be generated. Conclusively, therapeutic inhibition of classical NF-κB activation in macrophages may hamper the initiation of adaptive immunity.

scholarly journals Inhibition of Antigen-Specific and Nonspecific Stimulation of Bovine T and B Cells by Lymphostatin from Attaching and Effacing Escherichia coli

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Robin L. Cassady-Cain ◽  
Elizabeth A. Blackburn ◽  
Charlotte R. Bell ◽  
Elizaveta Elshina ◽  
Jayne C. Hope ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Content Type ◽  
E Coli ◽  
Stimulation Of

ABSTRACT Enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) are enteric bacterial pathogens of worldwide importance. Most EPEC and non-O157 EHEC strains express lymphostatin (also known as LifA), a chromosomally encoded 365-kDa protein. We previously demonstrated that lymphostatin is a putative glycosyltransferase that is important in intestinal colonization of cattle by EHEC serogroup O5, O111, and O26 strains. However, the nature and consequences of the interaction between lymphostatin and immune cells from the bovine host are ill defined. Using purified recombinant protein, we demonstrated that lymphostatin inhibits mitogen-activated proliferation of bovine T cells and, to a lesser extent, proliferation of cytokine-stimulated B cells, but not NK cells. It broadly affected the T cell compartment, inhibiting all cell subsets (CD4, CD8, WC-1, and γδ T cell receptor [γδ-TCR]) and cytokines examined (interleukin 2 [IL-2], IL-4, IL-10, IL-17A, and gamma interferon [IFN-γ]) and rendered T cells refractory to mitogen for a least 18 h after transient exposure. Lymphostatin was also able to inhibit proliferation of T cells stimulated by IL-2 and by antigen presentation using a Theileria-transformed cell line and autologous T cells from Theileria-infected cattle. We conclude that lymphostatin is likely to act early in T cell activation, as stimulation of T cells with concanavalin A, but not phorbol 12-myristate 13-acetate combined with ionomycin, was inhibited. Finally, a homologue of lymphostatin from E. coli O157:H7 (ToxB; L7095) was also found to possess comparable inhibitory activity against T cells, indicating a potentially conserved strategy for interference in adaptive responses by attaching and effacing E. coli.

scholarly journals Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 834
Author(s):  
Frederike A. Hartl ◽  
Jatuporn Ngoenkam ◽  
Esmeralda Beck-Garcia ◽  
Liz Cerqueira ◽  
Piyamaporn Wipa ◽  
...  
Keyword(s):  
T Cell ◽  
Ligand Binding ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Cooperative Interaction ◽  
Tcr Signaling ◽  
Binding Motifs ◽  
Adaptive Immune

The T cell antigen receptor (TCR) is expressed on T cells, which orchestrate adaptive immune responses. It is composed of the ligand-binding clonotypic TCRαβ heterodimer and the non-covalently bound invariant signal-transducing CD3 complex. Among the CD3 subunits, the CD3ε cytoplasmic tail contains binding motifs for the Src family kinase, Lck, and the adaptor protein, Nck. Lck binds to a receptor kinase (RK) motif and Nck binds to a proline-rich sequence (PRS). Both motifs only become accessible upon ligand binding to the TCR and facilitate the recruitment of Lck and Nck independently of phosphorylation of the TCR. Mutations in each of these motifs cause defects in TCR signaling and T cell activation. Here, we investigated the role of Nck in proximal TCR signaling by silencing both Nck isoforms, Nck1 and Nck2. In the absence of Nck, TCR phosphorylation, ZAP70 recruitment, and ZAP70 phosphorylation was impaired. Mechanistically, this is explained by loss of Lck recruitment to the stimulated TCR in cells lacking Nck. Hence, our data uncover a previously unknown cooperative interaction between Lck and Nck to promote optimal TCR signaling.

Abstract 442: Endoplasmic Reticulum (ER) Stress in the Subfornical Organ (SFO) Induces Peripheral Inflammation in Angiotensin II (Ang-II)-dependent Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Heinrich E Lob ◽  
Jiunn Song ◽  
Scott D Butler ◽  
Allyn L Mark ◽  
Robin L Davisson
Keyword(s):  
T Cell ◽  
Er Stress ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Fold Increase ◽  
Peripheral Inflammation ◽  
Ang Ii ◽  
Peripheral Vascular ◽  
Control Virus

The SFO is implicated in peripheral T cell activation and the genesis of Ang-II-dependent hypertension. Our recent studies show that ER stress in the SFO is also a key mechanism underlying the development of Ang-II hypertension. Because the ER is closely integrated with initiation of the adaptive immune response, we hypothesized that ER stress in the SFO contributes to peripheral inflammation in Ang-II hypertension. First, 5 days of intracerebroventricular (ICV) infusion of thapsigargin (Tg, 1 ug/day), a chemical ER stress inducer, caused a significant increase in CD3 + T cells in aortas (Tg: 11.9 ± 3.5 x 10 3 cells/aorta vs. Vehicle: 2.2 ± 0.7 x 10 3 cells/aorta , n = 6, p<0.05) and blood (Tg: 9.9 ± 1.8 x 10 4 cells/ mL vs. Vehicle: 2.9 ± 0.6 x 10 4 cells/ mL, n = 6, p<0.05). Furthermore, quantitative real-time PCR of SFO micropunches showed a 15-fold increase of TNF-α, a pro-inflammatory cytokine, a 3-fold increase of CCL5, a T cell attracting chemokine and a 3-fold increase in CD3, a T cell marker, (n = 4, p<0.05). To test the functional role of ER stress in the SFO in peripheral T cell activation, we targeted an adenovirus encoding GRP78 (AdGRP78), a molecular ER stress inhibitor, to this brain region during chronic systemic Ang-II infusion (600 ng/kg/min, 14 days). Our results demonstrate a significant reduction in T cell accumulation in aortas compared to control virus (AdLacZ) treatment (AdGRP78: 0.5 ± 0.07 x 10 4 cells/aorta vs. AdLacZ: 8.7 ± 2.1 x 10 4 cells/aorta, n = 6, p<0.05). These data show that 1) brain ER stress induces inflammation in the SFO and peripheral vascular T cell activation, and 2) ER stress in the SFO is linked to peripheral vascular T cell activation in Ang-II-dependent hypertension. These results suggest that ER stress and inflammation in the SFO induce peripheral vascular T cell activation and inflammation in Ang-II hypertension.

scholarly journals Mechanisms of Innate Lymphoid Cell and Natural Killer T Cell Activation during Mucosal Inflammation

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
David Nau ◽  
Nora Altmayer ◽  
Jochen Mattner
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Adaptive Immune System ◽  
Nkt Cells ◽  
Lymphoid Cells ◽  
Mucosal Inflammation ◽  
Natural Killer T

Mucosal surfaces in the airways and the gastrointestinal tract are critical for the interactions of the host with its environment. Due to their abundance at mucosal tissue sites and their powerful immunomodulatory capacities, the role of innate lymphoid cells (ILCs) and natural killer T (NKT) cells in the maintenance of mucosal tolerance has recently moved into the focus of attention. While NKT cells as well as ILCs utilize distinct transcription factors for their development and lineage diversification, both cell populations can be further divided into three polarized subpopulations reflecting the distinction into Th1, Th2, and Th17 cells in the adaptive immune system. While bystander activation through cytokines mediates the induction of ILC and NKT cell responses, NKT cells become activated also through the engagement of their canonical T cell receptors (TCRs) by (glyco)lipid antigens (cognate recognition) presented by the atypical MHC I like molecule CD1d on antigen presenting cells (APCs). As both innate lymphocyte populations influence inflammatory responses due to the explosive release of copious amounts of different cytokines, they might represent interesting targets for clinical intervention. Thus, we will provide an outlook on pathways that might be interesting to evaluate in this context.

scholarly journals Passively transferred IgG enhances humoral immunity to a red blood cell alloantigen in mice

2020 ◽  
Vol 4 (7) ◽  
pp. 1526-1537
Author(s):  
David R. Gruber ◽  
Amanda L. Richards ◽  
Heather L. Howie ◽  
Ariel M. Hay ◽  
Jenna N. Lebedev ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
T Cell Activation ◽  
Humoral Immunity ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Immunoglobulin M ◽  
Third Party ◽  
Cd4 T Cell ◽  
Specific Subset

Abstract Antibodies are typically thought of as the endpoint of humoral immunity that occur as the result of an adaptive immune response. However, affinity-matured antibodies can be present at the initiation of a new immune response, most commonly because of passive administration as a medical therapy. The current paradigm is that immunoglobulin M (IgM), IgA, and IgE enhance subsequent humoral immunity. In contrast, IgG has a “dual effect” in which it enhances responses to soluble antigens but suppresses responses to antigens on red blood cells (RBCs) (eg, immunoprophylaxis with anti-RhD). Here, we report a system in which passive antibody to an RBC antigen promotes a robust cellular immune response leading to endogenous CD4+ T-cell activation, germinal center formation, antibody secretion, and immunological memory. The mechanism requires ligation of Fcγ receptors on a specific subset of dendritic cells that results in CD4+ T-cell activation and expansion. Moreover, antibodies cross-enhance responses to a third-party antigen, but only if it is expressed on the same RBC as the antigen recognized by the antibody. Importantly, these observations were IgG subtype specific. Thus, these findings demonstrate that antibodies to RBC alloantigens can enhance humoral immunity in an IgG subtype-specific fashion and provide mechanistic elucidation of the enhancing effects.

scholarly journals Dynamic microtubules regulate cellular contractility during T-cell activation

2017 ◽  
Vol 114 (21) ◽  
pp. E4175-E4183 ◽  
Author(s):  
King Lam Hui ◽  
Arpita Upadhyaya
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Actin Polymerization ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Cell Receptor ◽  
Force Generation ◽  
Actin Dynamics ◽  
Bipolar Filament

T-cell receptor (TCR) triggering and subsequent T-cell activation are essential for the adaptive immune response. Recently, multiple lines of evidence have shown that force transduction across the TCR complex is involved during TCR triggering, and that the T cell might use its force-generation machinery to probe the mechanical properties of the opposing antigen-presenting cell, giving rise to different signaling and physiological responses. Mechanistically, actin polymerization and turnover have been shown to be essential for force generation by T cells, but how these actin dynamics are regulated spatiotemporally remains poorly understood. Here, we report that traction forces generated by T cells are regulated by dynamic microtubules (MTs) at the interface. These MTs suppress Rho activation, nonmuscle myosin II bipolar filament assembly, and actin retrograde flow at the T-cell–substrate interface. Our results suggest a novel role of the MT cytoskeleton in regulating force generation during T-cell activation.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

scholarly journals VISTA: A Target to Manage the Innate Cytokine Storm

2021 ◽  
Vol 11 ◽  
Author(s):  
Mohamed A. ElTanbouly ◽  
Yanding Zhao ◽  
Evelien Schaafsma ◽  
Christopher M. Burns ◽  
Rodwell Mabaera ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Constitutive Expression ◽  
Immune Checkpoints ◽  
Complete Suppression ◽  
Wide Range ◽  
The Impact

In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering via these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system. VISTA agonistic targeting profoundly changes the phenotype of human monocytes towards an anti-inflammatory cell state, as highlighted by striking suppression of the canonical markers CD14 and Fcγr3a (CD16), and the almost complete suppression of both the interferon I (IFN-I) and antigen presentation pathways. The insights from these very recent studies highlight the impact of VISTA agonistic targeting of myeloid cells, and its potential therapeutic implications in the settings of hyperinflammatory responses such as cytokine storms, driven by dysregulated immune responses to viral infections (with a focus on COVID-19) and autoimmune diseases. Collectively, these findings suggest that the VISTA pathway plays a conserved, non-redundant role in myeloid cell function.

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