scholarly journals The Activation Status of Neuroantigen-specific T Cells in the Target Organ Determines the Clinical Outcome of Autoimmune Encephalomyelitis

2004 ◽  
Vol 199 (2) ◽  
pp. 185-197 ◽  
Author(s):  
Naoto Kawakami ◽  
Silke Lassmann ◽  
Zhaoxia Li ◽  
Francesca Odoardi ◽  
Thomas Ritter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Response ◽  
T Cell Activation ◽  
Cell Activation ◽  
Expression Patterns ◽  
Target Tissue ◽  
Autoimmune Encephalomyelitis ◽  
Effector T Cell ◽  
Green Fluorescent

The clinical picture of experimental autoimmune encephalomyelitis (EAE) is critically dependent on the nature of the target autoantigen and the genetic background of the experimental animals. Potentially lethal EAE is mediated by myelin basic protein (MBP)–specific T cells in Lewis rats, whereas transfer of S100β- or myelin oligodendrocyte glycoprotein (MOG)–specific T cells causes intense inflammatory response in the central nervous system (CNS) with minimal disease. However, in Dark Agouti rats, the pathogenicity of MOG-specific T cells resembles the one of MBP-specific T cells in the Lewis rat. Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue. Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein+ T cells into the CNS were similar. However, exclusively highly pathogenic T cells were significantly reactivated within the CNS. Without local effector T cell activation, production of monocyte chemoattractants was insufficient to initiate and propagate a full inflammatory response. Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3ζ expression

Blood ◽  
2001 ◽  
Vol 97 (12) ◽  
pp. 3851-3859 ◽  
Author(s):  
Sandeep Krishnan ◽  
Vishal G. Warke ◽  
Madhusoodana P. Nambiar ◽  
Henry K. Wong ◽  
George C. Tsokos ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Tyrosine Phosphorylation ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Effector T Cells ◽  
T Cell Differentiation ◽  
Effector T Cell

Human effector T cells have been difficult to isolate and characterize due to their phenotypic and functional similarity to the memory subset. In this study, a biochemical approach was used to analyze human effector CD4 T cells generated in vitro by activation with anti-CD3 and autologous monocytes for 3 to 5 days. The resultant effector cells expressed the appropriate activation/differentiation markers and secreted high levels of interferon γ (IFN-γ) when restimulated. Biochemically, effector CD4 T cells exhibited increases in total intracellular tyrosine phosphorylation and effector-associated phosphorylated species. Paradoxically, these alterations in tyrosine phosphorylation were concomitant with greatly reduced expression of CD3ζ and CD3ε signaling subunits coincident with a reduction in surface T-cell receptor (TCR) expression. Because loss of CD3ζ has also been detected in T cells isolated ex vivo from individuals with cancer, chronic viral infection, and autoimmune diseases, the requirements and kinetics of CD3ζ down-regulation were examined. The loss of CD3ζ expression persisted throughout the course of effector T-cell differentiation, was reversible on removal from the activating stimulus, and was modulated by activation conditions. These biochemical changes occurred in effector T cells generated from naive or memory CD4 T-cell precursors and distinguished effector from memory T cells. The results suggest that human effector T-cell differentiation is accompanied by alterations in the TCR signal transduction and that loss of CD3ζ expression may be a feature of chronic T-cell activation and effector generation in vivo.

scholarly journals Regulatory T cells sense effector T‐cell activation through synchronized JunB expression

FEBS Letters ◽  
2019 ◽  
Vol 593 (10) ◽  
pp. 1020-1029 ◽  
Author(s):  
Jingxia Wu ◽  
Sicong Ma ◽  
Agnes Hotz‐Wagenblatt ◽  
Peter Angel ◽  
Kerstin Mohr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Effector T Cell

Juzentaihoto Exerts Anti-Allergic Effects by Inhibiting Effector T-Cell Activation and Inducing and/or Activating Regulatory T Cells in a Murine Model of Contact Hypersensitivity

2021 ◽  
pp. 1-13
Author(s):  
Atsushi Tsuge ◽  
Sho Yonekura ◽  
Satomi Watanabe ◽  
Yuta Kurosaki ◽  
Shinsuke Hisaka ◽  
...  
Keyword(s):  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Effector T Cells ◽  
Contact Hypersensitivity ◽  
Dependent Manner ◽  
Effector T Cell

<b><i>Background:</i></b> Juzentaihoto (JTT) is a Kampo prescription that has been used clinically for treating skin diseases such as atopic dermatitis in Japan. We have previously studied the anti-allergic effects of JTT on 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) in mice and demonstrated that it significantly suppresses ear swelling in a dose-dependent manner. However, the mechanism underlying the anti-allergic actions of JTT is obscure. <b><i>Methods:</i></b> We investigated the mechanism underlying the anti-allergic effects of JTT using a TNCB-induced murine CHS model and adoptive cell transfer experiments. <b><i>Results:</i></b> We showed that the anti-allergic effects of JTT are due to inhibition of effector T-cell activation and induction and/or activation of regulatory T cells. Furthermore, ex vivo experiments confirmed the effect of JTT on the activation of effector T cells and regulatory T cells, as interferon-γ production decreased, whereas interleukin (IL)-10 production increased, in the cultured lymphocytes obtained from 5% TNCB-sensitized mice treated with anti-CD3ε and anti-CD28 monoclonal antibodies. Flow cytometry showed that the CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup>, CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>−</sup>, and CD8<sup>+</sup>CD122<sup>+</sup> cell population increased after oral administration of JTT. Finally, the anti-allergic effect of JTT by inducing and/or activating regulatory T cells (Tregs) was confirmed to be mediated by IL-10 through in vivo neutralization experiments with anti-IL-10 monoclonal antibodies. <b><i>Conclusion:</i></b> We suggested that JTT exerts anti-allergic effects by regulating the activation of effector T cells and Tregs involved in murine CHS model.

Secondary Lymphoid Tissues Are Not Required for the Induction of GVHD Following Allogeneic BMT: A Shifting Paradigm for T Cell Allo-Activation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3170-3170
Author(s):  
Ines A. Silva ◽  
Krystyna Olkiewicz ◽  
Jacquelyn M. Fisher ◽  
Meghana N. Chaudhary ◽  
Kevin Vannella Vannella ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Major Complication ◽  
Scoring Systems ◽  
Lymphoid Tissues ◽  
Target Tissue

Abstract Allogeneic (allo) bone marrow transplantation (BMT) is the only curative option for many patients with malignant and non-malignant diseases. Acute graft versus host disease (GVHD) is the major complication of allo-BMT and limits the utility of this treatment strategy. The induction of GVHD fundamentally depends upon the activation of donor T cells by host antigen presenting cells (APCs), and the prevailing hypothesis is that these critical interactions occur in secondary lymphoid organs, such as lymph nodes (LN) Peyer’s patches (PP), and spleen (SP). We tested this hypothesis by using a well established, MHC disparate, murine SCT system (Balb/c → B6) and homozygous aly/aly (alymphoplasia) mice that are deficient in all LN and PP and heterozygous aly/+ littermate controls. Lethally irradiated, splenectomized, aly/aly mice (LN/PP/SP −/ −) and aly/+ sham mice (LN/PP/SP +/+) received BMT either from syngeneic (aly/aly) or allo (Balb/c) donors. In some experiments, wild-type B6 recipients of B6 or Balb/c BMT served as additional negative and positive GVHD controls respectively. The severity of GVHD was assessed by survival and well-described scoring systems of both clinical and target organ disease. As expected, greater than 95% of syngeneic (syn) BMT recipients survived and were indistinguishable from naïve, un-transplanted controls, whereas LN/PP/SP +/+ mice receiving allo-BMT showed significant signs of GVHD with ~40% mortality by day 49. All LN/PP/SP −/ − allo-BMT recipients also survived, but surprisingly, examination demonstrated that they too developed significant clinical GVHD compared to syn controls (score: 3.2 vs. 0.85) that was comparable in severity to LN/PP/SP +/+ mice (3.1). Moreover, histopathologic analysis demonstrated that LN/PP/SP −/ − allo-BMT recipients developed significantly greater GVHD target tissue damage in the liver, intestinal tract and skin compared to syn controls. In fact, LN/PP/SP −/ − allo-BMT recipients developed more severe hepatic GVHD compared to allo littermate (LN/PP/SP +/+) controls (30.8±1.9 vs. 20.7±2.2; p < 0.01). Similar differences in liver GVHD was also seen between allo groups as early as day 7 (16.0±2.2 vs. 7.3±0.9; p < 0.01). We next tested the ability of host aly/aly and aly/+ APCs to stimulate donor Balb/c T cells in vitro. No differences in proliferation, IFN γ production or CTL generation were detected, thus showing that the allo-stimulatory capacity of host APCs was not different between groups. In order to ascertain what extra-lymphoid host tissues might serve as initial sites for allo-antigen exposure, we examined donor T cell expansion (CD3+), activation (CD69+) and proliferation (CFSE) in the bone marrow compartment 3 days after BMT. We found that in each case, LN/PP/SP −/ − allo-BMT recipients had significantly higher numbers / divisions compared to allo, littermate, (LN/PP/SP +/+) controls. Collectively, these data challenge the paradigm that secondary lymphoid tissues are required for GVHD induction, and suggest that the bone marrow may represent an alternative site for allo-antigen recognition and donor T cell activation.

scholarly journals The Serine Protease CD26/DPP4 in Non-Transformed and Malignant T Cells

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5947
Author(s):  
Guranda Chitadze ◽  
Ulrike Wehkamp ◽  
Ottmar Janssen ◽  
Monika Brüggemann ◽  
Marcus Lettau
Keyword(s):  
T Cells ◽  
T Cell ◽  
Serine Protease ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Transmembrane Protein ◽  
Expression Patterns ◽  
Soluble Form ◽  
Interaction Partners

CD26/Dipeptidylpeptidase 4 is a transmembrane serine protease that cleaves off N-terminal dipeptides. CD26/DPP4 is expressed on several immune cell types including T and NK cells, dendritic cells, and activated B cells. A catalytically active soluble form of CD26/DPP4 can be released from the plasma membrane. Given its wide array of substrates and interaction partners CD26/DPP4 has been implicated in numerous biological processes and effects can be dependent or independent of its enzymatic activity and are exerted by the transmembrane protein and/or the soluble form. CD26/DPP4 has been implicated in the modulation of T-cell activation and proliferation and CD26/DPP4-positive T cells are characterized by remarkable anti-tumor properties rendering them interesting candidates for T cell-based immunotherapies. Moreover, especially in cutaneous T-cell lymphoma CD26/DPP4 expression patterns emerged as an established marker for diagnosis and treatment monitoring. Surprisingly, besides a profound knowledge on substrates, interaction partners, and associated signal transduction pathways, the precise role of CD26/DPP4 for T cell-based immune responses is only partially understood.

scholarly journals Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Lanman Xu ◽  
Xiaofang Wang ◽  
Yan Chen ◽  
Lynn Soong ◽  
Yongping Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Liver Injury ◽  
Viral Hepatitis ◽  
T Cell Activation ◽  
Cell Activation ◽  
Metformin Treatment ◽  
Effector T Cell ◽  
Mitochondrial Functions ◽  
Mtorc1 Signaling

Metformin is not only the first-line medication for the treatment of type 2 diabetes, but it is also effective as an anti-inflammatory, anti-oxidative and anti-tumor agent. However, the effect of metformin during viral hepatitis remains elusive. Using an adenovirus (Ad)-induced viral hepatitis mouse model, we found that metformin treatment significantly attenuated liver injury, with reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) levels and liver histological changes, presumably via decreased effector T cell responses. We then demonstrated that metformin reduced mTORC1 activity in T cells from infected mice, as evidenced by decreased phosphorylation of ribosome protein S6 (p-S6). The inhibitory effects on the mTORC1 signaling by metformin was dependent on the tuberous sclerosis complex 1 (TSC1). Mechanistically, metformin treatment modulated the phosphorylation of dynamin-related protein 1 (Drp-1) and mitochondrial fission 1 protein (FIS1), resulting in increased mass in effector T cells. Moreover, metformin treatment promoted mitochondrial superoxide production, which can inhibit excessive T cell activation in viral hepatitis. Together, our results revealed a protective role and therapeutic potential of metformin against liver injury in acute viral hepatitis via modulating effector T cell activation via regulating the mTORC1 pathway and mitochondrial functions.

scholarly journals Signaling through polymerization and degradation: Analysis and simulations of T cell activation mediated by Bcl10

2020 ◽  
Author(s):  
Leonard Campanello ◽  
Maria K. Traver ◽  
Hari Shroff ◽  
Brian C. Schaefer ◽  
Wolfgang Losert
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Super Resolution ◽  
Effector T Cells ◽  
Effector T Cell ◽  
Filament Assembly

AbstractThe adaptive immune system serves as a potent and highly specific defense mechanism against pathogen infection. One component of this system, the effector T cell, facilitates pathogen clearance upon detection of specific antigens by the T cell receptor (TCR). A critical process in effector T cell activation is transmission of signals from the TCR to a key transcriptional regulator, NF-κB. The transmission of this signal involves a highly dynamic process in which helical filaments of Bcl10, a key protein constituent of the TCR signaling cascade, undergo competing processes of polymeric assembly and macroautophagy-dependent degradation. Through computational analysis of three-dimensional super-resolution microscopy data, we quantitatively characterized TCR-stimulated Bcl10 filament assembly and length dynamics, demonstrating that filaments become shorter over time. Additionally, we developed an image-based bootstrap-like resampling method to quantitatively demonstrate preferred association between autophagosomes and Bcl10-filament ends and punctate-Bcl10 structures, implying that autophagosome-driven macroautophagy is directly responsible for Bcl10 filament shortening. We probe Bcl10 polymerization-depolymerization dynamics with a stochastic Monte-Carlo simulation of nucleation-limited filament assembly and degradation, and we show that high probabilities of filament nucleation in response to TCR engagement could provide the observed robust, homogeneous, and tunable response dynamic. Furthermore, the speed of autophagic degradation of filaments preferentially at filament ends provides effective regulatory control. Taken together, these data suggest that Bcl10 filament growth and degradation act as an excitable system that provides a digital response mechanism and the reliable timing critical for T cell activation and regulatory processes.Author SummaryThe immune system serves to protect organisms against pathogen-mediated disease. While a strong immune response is needed to eliminate pathogens in host organisms, immune responses that are too robust or too persistent can trigger autoimmune disorders, cancer, and a variety of additional serious human pathologies. Thus, a careful balance of activating and inhibitory mechanisms are necessary to prevent detrimental health outcomes of immune responses. For example, activated effector T cells marshal the immune response and direct killing of pathogen-infected cells; however, effector T cells that are chronically activated can damage and destroy healthy tissue. Here, we study an important internal activation pathway in effector T cells that involves the growth and counterbalancing degradation (via a process called macroautophagy) of filamentous cytoplasmic signaling structures. We utilize image analysis of 3-D super-resolution images and Monte Carlo simulations to study a key signal-transduction protein, Bcl10. We found that the speed of filament degradation has the greatest effect on the magnitude and duration of the response, implying that pharmaceutical interventions aimed at macroautophagy may have substantial impact on effector T cell function. Given that filamentous structures are utilized in numerous immune signaling pathways, our analysis methods could have broad applicability in the signal transduction field.

Abstract 5448: Regulatory T Cells Control Post-Ischemic Neovascularization

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yasmine Zouggari ◽  
Hafid Ait-Oufella ◽  
Ludovic Waeckel ◽  
José Vilar ◽  
Céline Loinard ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Inflammatory Response ◽  
Treg Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Critical Role ◽  
Vessel Growth ◽  
Deficient Mice

CD4+ and CD8+ T lymphocytes are key regulators of post-ischemic neovascularization. T cell activation is promoted by two major costimulatory signalings: the CD28/B7 and the CD40ligand-CD40 pathways. Interestingly, CD28 interactions with the structurally related ligands B7–1 and B7–2 are also required for the generation and homeostasis of CD4+CD25+ regulatory T cells (Treg), which play a critical role in the suppression of immune responses and the control of T-cell homeostasis. We hypothesized that Treg cell activation may modulate the immuno-inflammatory response to ischemic injury, leading to alteration of post-ischemic vessel growth. Ischemia was induced by right femoral artery ligation in CD28-, B7–1/2- or CD40-deficient mice (n=10 per group). CD40 deficiency did not affect Treg levels and led to significant reduction in post-ischemic inflammatory response and vessel growth. In contrast, at day 21 after ischemia, angiographic score, foot perfusion, and capillary density were increased by 2.0-, 1.2-, and 1.8-fold respectively in CD28-deficient mice, which show profound reduction in Treg, compared to controls. Similarly, disruption of B7–1/2 signaling and subsequent Treg deletion significantly enhanced post-ischemic neovascularization. These effects were associated with enhanced accumulation of CD3-positive T cells and Mac-3 positive macrophages in the ischemic leg of CD28−/− or B7−/− mice compared with controls. Proinflammatory cytokines, IL-1β, TNF-α and IL-6, were also upregulated and antiinflammatory mediators, IL-10 and TGF-β1 downregulated in the ischemic legs of CD28−/− or B7−/− mice. Finally, treatment of CD28−/− mice with the nonmitogenic anti-CD3 monoclonal antibody enhanced expression of the regulatory T-cell marker Foxp3 in blood and ischemic tissue of CD28−/− mice, led to reduction in post-ischemic inflammatory response and neovascularization in CD28-deficient mice. In conclusion, endogenous Treg cell response controls post-ischemic neovascularization.

scholarly journals Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation

2014 ◽  
Vol 211 (12) ◽  
pp. 2467-2479 ◽  
Author(s):  
Heeyoung Yang ◽  
Quan Qiu ◽  
Beixue Gao ◽  
Sinyi Kong ◽  
Zhenghong Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
B Lymphocyte ◽  
Cd4 T Cell ◽  
Autoimmune Encephalomyelitis ◽  
Mhc I ◽  
Mhc Ii ◽  
Maturation Protein

The ubiquitin pathway plays critical roles in antigen presentation. However, the ubiquitin ligases that regulate MHC gene transcription remain unidentified. We showed that the ubiquitin ligase Hrd1, expression of which is induced by Toll-like receptor (TLR) stimulation, is required for MHC-II but not MHC-I transcription in dendritic cells (DCs). Targeted Hrd1 gene deletion in DCs diminished MHC-II expression. As a consequence, Hrd1-null DCs failed to prime CD4+ T cells without affecting the activation of CD8+ T cells. Hrd1 catalyzed ubiquitination and degradation of the transcriptional suppressor B lymphocyte–induced maturation protein 1 (BLIMP1) to promote MHC-II expression. Genetic suppression of Hrd1 function in DCs protected mice from myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE). We identified Hrd1-mediated BLIMP1 ubiquitination as a previously unknown mechanism in programming DC for CD4+ T cell activation during inflammation.

scholarly journals T-cell receptor– and CD28-induced Vav1 activity is required for the accumulation of primed T cells into antigenic tissue

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3696-3705 ◽  
Author(s):  
Rachel David ◽  
Liang Ma ◽  
Aleksandar Ivetic ◽  
Aya Takesono ◽  
Anne J. Ridley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Receptor ◽  
Target Tissue ◽  
Nucleotide Exchange ◽  
Cell Immunity

Abstract Localization of primed T cells to antigenic tissue is essential for the development of effective immunity. Together with tissue-selective homing molecules, T-cell receptor (TCR)– and CD28-mediated signals have been shown to promote transendothelial migration of specific T cells into nonlymphoid antigen-rich tissue. However, the cellular and molecular requirements for T-cell accumulation to target tissue following their recruitment are largely undefined. The guanine nucleotide exchange factor (GEF) Vav1 has an integral role in coupling TCR and CD28 to signaling pathways that regulate T-cell activation and migration. Here, we have investigated the contribution of TCR- and CD28-induced Vav1 activity to the trafficking and localization of primed HY-specific CD4+ T cells to antigenic sites. Severe migratory defects displayed by Vav1−/− T cells in vitro were fully compensated by a combination of shear flow and chemokines, leading to normal recruitment of Vav1−/− T cells in vivo. In contrast, Vav1−/− T-cell retention into antigen-rich tissue was severely impaired, reflecting T cells' inability to engage in sustained TCR- and CD28-mediated interactions with tissue-resident antigen-presenting cells (APCs). This novel function of APC-induced, and TCR- and CD28-mediated Vav1 activity in the regulation of effector T-cell immunity highlights its potential as a therapeutic target in T cell–mediated tissue damage.

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