scholarly journals Experimental Infection with Trypanosoma cruzi Increases the Population of CD8+, but not CD4+, Immunoglobulin G Fc Receptor-Positive T Lymphocytes

2005 ◽  
Vol 73 (8) ◽  
pp. 5048-5052 ◽  
Author(s):  
Andrea Henriques-Pons ◽  
Bianca P. Olivieri ◽  
Gabriel M. Oliveira ◽  
Marc Daëron ◽  
Tania C. de Araújo-Jorge
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Trypanosoma Cruzi ◽  
Immunoglobulin G ◽  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Inflammatory Infiltration ◽  
Functional Roles

ABSTRACT It is well established that activating-type Fc receptors for immunoglobulin G (FcγR), such as FcγRI and FcγRIII, are essential for inducing inflammatory responses. On the other hand, a unique inhibitory FcγR, FcγRIIB, inhibits intracellular signaling upon engagement of immunoglobulin G-immune complexes, suppressing inflammation and autoimmunity. The expression of FcγRIIB on B lymphocytes, natural killer cells, macrophages, mast cells, and a number of other cell types has been demonstrated for many years. However, the expression on T lymphocytes is probably restricted to activated cells in a narrow window of time. The controversy regarding the FcγR expression on T lymphocytes is attributable to considerable heterogeneity of cellular subpopulations and activation stages during immune responses in vivo. We addressed here this question by using mice experimentally infected with Trypanosoma cruzi, and we found an increase in the CD8+ FcγR+ population but not in the CD4+ FcγR+ population. Moreover, CD8+ FcγR+ T cells predominantly composed the cardiac inflammatory infiltration induced by the infection. These results indicate a novel pattern of FcγR expression on T cells in a pathological situation, and possible functional roles of this phenomenon are discussed.

A Mouse Model for XLP-2 Disease Uncovers a Critical Function for IL-1beta and TNF in Driving Hyper-Inflammation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1403-1403
Author(s):  
Philipp J. Jost ◽  
Monica Yabal ◽  
Heiko Adler ◽  
Nathalie Knies ◽  
Christina Groß ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Lymphocytes ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Human Peripheral Blood ◽  
Critical Function ◽  
Deficient Mice

Abstract The hyper-inflammatory syndrome X-linked lymphoproliferative syndrome type 2 (XLP-2) is defined by mutations in BIRC4 (XIAP). XLP-2 is often diagnosed in paediatric patients and is characterized by hyper-inflammation triggered by common viral infections. Symptoms include splenomegaly, HLH, fevers, and chronic haemorrhagic colitis among others. Recent work has also shown that mutations in BIRC4 predispose to the development of early-onset IBD, which is not necessarily associated with symptoms of systemic hyper-inflammation. Symptoms of XLP-2 are mostly attributed to the aberrant activation of macrophages and dendritic cells (DC) and the subsequent accumulation of activated T-lymphocytes. We have characterized the inflammatory response of mice deficient for BIRC4 (XIAP) to viral infections with the murine herpes virus 68 (MHV-68) as the closest murine model for human EBV-driven mononucleosis. Xiap-/- mice were capable of clearing the virus normally during early infection (day 6, 16), but failed to do so during the course of the infection measured as elevated viral genomic loads during late (day 43) and very late (day 84) latency. Xiap-/- mice responded to intranasal application of the virus with systemic hyper-inflammation exemplified by elevated IL-1beta levels, splenomegaly and increased activation of peripheral T lymphocytes such as CD4+ effector T cells, regulatory T cells (Treg), and IFNg+ T cells. In previous work, we have shown that TNF is critically required to drive the hyper-inflammatory phenotype of macrophages and dendritic cells of XIAP-deficient mice. Indeed, genetic deletion of TNF in vivo or, alternatively, anti-TNF treatment in vivo using Eternacept (Enbrel) ameliorated the symptoms of XIAP-deficient mice in response to viral infection. Elevated IL-1beta levels were also observed in human peripheral blood-derived monocytes from XLP-2 patients (7 patients from 5 different families) when compared to healthy controls. In conclusion, this data supports the notion that anti-TNF treatment might be able to ameliorate the hyper-inflammatory responses in XLP-2 patients, when used early during an infection. Disclosures No relevant conflicts of interest to declare.

scholarly journals Migration and Function of Antigen-Primed Nonpolarized T Lymphocytes in Vivo

2001 ◽  
Vol 193 (8) ◽  
pp. 987-994 ◽  
Author(s):  
Giandomenica Iezzi ◽  
Doris Scheidegger ◽  
Antonio Lanzavecchia
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Lymph Nodes ◽  
Cell Types ◽  
Cell Receptor ◽  
Effector Function ◽  
Antigenic Stimulation ◽  
Secondary Response ◽  
Th2 Cells

Upon antigenic stimulation, naive T lymphocytes proliferate and a fraction of the activated cells acquire a T helper cell type 1 (Th1) or Th2 phenotype as well as the capacity to migrate to inflamed tissues. However, the antigen-primed T cells that receive a short T cell receptor (TCR) stimulation do not acquire effector function and remain in a nonpolarized state. Using TCR transgenic CD4+ T cells in an adoptive transfer system, we compared the in vivo migratory capacities of naive, nonpolarized, Th1 or Th2 cells. Although all cell types migrated to the spleen, only naive and nonpolarized T cells efficiently migrated to lymph nodes. In addition Th1, but not Th2, migrated to inflamed tissues. In the lymph nodes, nonpolarized T cells proliferated and acquired effector function in response to antigenic stimulation, displaying lower activation threshold and faster kinetics compared with naive T cells. These results suggest that nonpolarized T cells are in an intermediate state of differentiation characterized by lymph node homing capacity and increased responsiveness that allows them to mount a prompt and effective secondary response.

scholarly journals TNFα SIGNALLING IN THE CUTANEOUS IMMUNE NETWORK INSTRUCTS LOCAL Th17 ALLERGEN-SPECIFIC INFLAMMATORY RESPONSES IN ATOPIC DERMATITIS

2021 ◽  
Author(s):  
Sofia Sirvent ◽  
Andres F Vallejo ◽  
Emma Corden ◽  
Ying Teo ◽  
James Davies ◽  
...  
Keyword(s):  
T Cells ◽  
Atopic Dermatitis ◽  
Human Skin ◽  
Inflammatory Responses ◽  
Allergen Challenge ◽  
Cell Types ◽  
Nucleotide Polymorphisms ◽  
Antioxidant Defences ◽  
Skin Cell

Accurate regulation of cutaneous immunity is fundamental for human health and quality of life but is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance vs inflammation in human skin, we set up a human in vivo allergen challenge study, exposing patients with atopic dermatitis (AD) to house dust mite (HDM). Analyses of transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of resident and infiltrating immune cells indicated that inflammatory responses to HDM were associated with immune activation in Langerhans cells (LCs) and cutaneous T cells. High basal level of TNFα production by cutaneous Th17 T cells predisposed to an inflammatory reaction and resulted in formation of hub structures where LCs and T cells interacted, leading to loss of functional programming in LCs. Additionally, single nucleotide polymorphisms in MT1X gene associated with enhanced expression of metallothioneins and transcriptional programmes encoding antioxidant defences across skin cell types in non-reactive patients, were protective against T cell mediated inflammation. Our results provide a unique insight into the dynamics of immune regulation in the human skin and define regulatory circuits that can be harnessed to improve skin health and treat disease.

scholarly journals Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dehua Lu ◽  
Yanpu Wang ◽  
Ting Zhang ◽  
Feng Wang ◽  
Kui Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes ◽  
Pet Imaging ◽  
Stage Migration ◽  
Cell Transfer ◽  
Tumor Infiltration ◽  
Antitumor Effects

Abstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. Methods We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). Results CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. Conclusion These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens. Graphic Abstract

scholarly journals Enhancing the Nrf2 Antioxidant Signaling Provides Protection Against Trichloroethene-mediated Inflammation and Autoimmune Response

2020 ◽  
Vol 175 (1) ◽  
pp. 64-74 ◽  
Author(s):  
Nivedita Banerjee ◽  
Hui Wang ◽  
Gangduo Wang ◽  
M Firoze Khan
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Autoimmune Response ◽  
Mediated Effects ◽  
Antioxidant Gene Expression ◽  
Responsive Element

Abstract Trichloroethene (trichloroethylene, TCE) and one of its reactive metabolites dichloroacetyl chloride (DCAC) are associated with the induction of autoimmunity in MRL+/+ mice. Although oxidative stress plays a major role in TCE-/DCAC-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Nuclear factor (erythroid-derived 2)-like2 (Nrf2) is an oxidative stress-responsive transcription factor that binds to antioxidant responsive element (ARE) and provides protection by regulating cytoprotective and antioxidant gene expression. However, the potential of Nrf2 in the regulation of TCE-/DCAC-mediated autoimmunity is not known. This study thus focused on establishing the role of Nrf2 and consequent inflammatory responses in TCE-/DCAC-mediated autoimmunity. To achieve this, we pretreated Kupffer cells (KCs) or T cells with/without tert-butylhydroquinone (tBHQ) followed by treatment with DCAC. In both KCs and T cells, DCAC treatment significantly downregulated Nrf2 and HO-1 expression along with induction of Keap-1 and caspase-3, NF-κB (p65), TNF-α, and iNOS, whereas pretreatment of these cells with tBHQ attenuated these responses. The in vitro findings were further verified in vivo by treating female MRL+/+ mice with TCE along with/without sulforaphane. TCE exposure in mice also led to reduction in Nrf2 and HO-1 but increased phospho-NF-κB (p-p65) and iNOS along with increased anti-dsDNA antibodies. Interestingly, sulforaphane treatment led to amelioration of TCE-mediated effects, resulting in Nrf2 activation and reduction in inflammatory and autoimmune responses. Our results show that TCE/DCAC mediates an impairment in Nrf2 regulation. Attenuation of TCE-mediated autoimmunity via activation of Nrf2 supports that antioxidants sulforaphane/tBHQ could be potential therapeutic agents for autoimmune diseases.

scholarly journals Gastric Hyperplasia and Increased Proliferative Responses of Lymphocytes in Mice Lacking the COOH-terminal Ankyrin Domain of NF-κB2

1997 ◽  
Vol 186 (7) ◽  
pp. 999-1014 ◽  
Author(s):  
Hideaki Ishikawa ◽  
Daniel Carrasco ◽  
Estefania Claudio ◽  
Rolf-Peter Ryseck ◽  
Rodrigo Bravo
Keyword(s):  
T Cells ◽  
Lymphocyte Proliferation ◽  
Cytokine Production ◽  
Cell Types ◽  
Homozygous Deletion ◽  
Binding Activity ◽  
Activated T Cells ◽  
Physiological Relevance

The nfkb2 gene encodes the p100 precursor which produces the p52 protein after proteolytic cleavage of its COOH-terminal domain. Although the p52 product can act as an alternative subunit of NF-κB, the p100 precursor is believed to function as an inhibitor of Rel/NF-κB activity by cytoplasmic retention of Rel/NF-κB complexes, like other members of the IκB family. However, the physiological relevance of the p100 precursor as an IκB molecule has not been understood. To assess the role of the precursor in vivo, we generated, by gene targeting, mice lacking p100 but still containing a functional p52 protein. Mice with a homozygous deletion of the COOH-terminal ankyrin repeats of NF-κB2 (p100−/−) had marked gastric hyperplasia, resulting in early postnatal death. p100−/− animals also presented histopathological alterations of hematopoietic tissues, enlarged lymph nodes, increased lymphocyte proliferation in response to several stimuli, and enhanced cytokine production in activated T cells. Dramatic induction of nuclear κB–binding activity composed of p52-containing complexes was found in all tissues examined and also in stimulated lymphocytes. Thus, the p100 precursor is essential for the proper regulation of p52-containing Rel/NF-κB complexes in various cell types and its absence cannot be efficiently compensated for by other IκB proteins.

scholarly journals Benznidazole Treatment following Acute Trypanosoma cruzi Infection Triggers CD8+ T-Cell Expansion and Promotes Resistance to Reinfection

2002 ◽  
Vol 46 (12) ◽  
pp. 3790-3796 ◽  
Author(s):  
Bianca Perdigão Olivieri ◽  
Vinícius Cotta-de-Almeida ◽  
Tania Araújo-Jorge
Keyword(s):  
T Lymphocytes ◽  
Trypanosoma Cruzi ◽  
Immune Regulation ◽  
Immune Dysregulation ◽  
Direct Role ◽  
Parasite Replication ◽  
The Impact ◽  
Shed Light ◽  
Cruzi Infection

ABSTRACT Many studies have shed light on the mechanisms underlying both immunoprotection and immune dysregulation arising after Trypanosoma cruzi infection. However, little is known about the impact of benznidazole (N-benzyl-2-nitroimidazole acetamide), the drug available for clinical treatment of the infection, on the immune system in the infected host. In the present study we investigated the effect of benznidazole therapy on the lymphoid compartment during the course of experimental T. cruzi infection. Although amelioration of a variety of clinical and parasitological signs was observed in treated mice, amelioration of splenocyte expansion was not detected. Interestingly, this sustained splenomegaly observed in benznidazole-treated mice showed a preferential expansion of CD8+ T lymphocytes. Moreover, although benznidazole treatment blocked the expansion of recently activated CD4+ and CD8+ T cells seen in infected hosts, benznidazole treatment led to a selective expansion of effector and memory CD8+ T lymphocytes in association with a lower rate of apoptosis. In addition, the surviving treated animals were protected from reinfection. Together, these data suggest that, in addition to its well-known direct role in blocking parasite replication in vivo, benznidazole appears to directly affect immune regulation in T. cruzi-infected hosts.

Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase–dependent induction of Socs-3

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3512-3519 ◽  
Author(s):  
Roberta Caruso ◽  
Carmine Stolfi ◽  
Massimiliano Sarra ◽  
Angelamaria Rizzo ◽  
Massimo C. Fantini ◽  
...  
Keyword(s):  
Map Kinase ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Human Peripheral Blood ◽  
Serum Levels ◽  
Cell Types ◽  
P38 Map Kinase ◽  
Negative Regulator ◽  
Therapeutic Implications

Abstract IL-25, a member of the IL-17 cytokine family, is known to enhance Th2-like responses associated with increased serum levels of IgE, IgG1, IgA, blood eosinophilia, and eosinophilic infiltrates in various tissues. However, IL-25 also abrogates inflammatory responses driven by Th17 cells. However, the cell types that respond to IL-25 and the mechanisms by which IL-25 differentially regulates immune reactions are not well explored. To identify potential targets of IL-25, we initially examined IL-25 receptor (IL-25R) in human peripheral blood cells. IL-25R was predominantly expressed by CD14+ cells. We next assessed the functional role of IL-25 in modulating the response of CD14+ cells to various inflammatory signals. CD14+ cells responded to IL-25 by down-regulating the synthesis of inflammatory cytokines induced by toll-like receptor (TLR) ligands and inflammatory cytokines. Inhibition of cytokine response by IL-25 occurred via a p38 Map kinase–driven Socs-3–dependent mechanism. In vivo, IL-25 inhibited monocyte-derived cytokines and protected against LPS-induced lethal endotoxemia in mice. These data indicate that IL-25 is a negative regulator of monocyte proinflammatory cytokine responses, which may have therapeutic implications.

scholarly journals Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth.

1986 ◽  
Vol 163 (5) ◽  
pp. 1037-1050 ◽  
Author(s):  
J H Kehrl ◽  
L M Wakefield ◽  
A B Roberts ◽  
S Jakowlew ◽  
M Alvarez-Mon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Transforming Growth Factor Beta ◽  
Potential Role ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Tgf Beta ◽  
Activated T Cells ◽  
Growth Factor Beta

This study examines the potential role of transforming growth factor beta (TGF-beta) in the regulation of human T lymphocyte proliferation, and proposes that TGF-beta is an important autoregulatory lymphokine that limits T lymphocyte clonal expansion, and that TGF-beta production by T lymphocytes is important in T cell interactions with other cell types. TGF-beta was shown to inhibit IL-2-dependent T cell proliferation. The addition of picograms amounts of TGF-beta to cultures of IL-2-stimulated human T lymphocytes suppressed DNA synthesis by 60-80%. A potential mechanism of this inhibition was found. TGF-beta inhibited IL-2-induced upregulation of the IL-2 and transferrin receptors. Specific high-affinity receptors for TGF-beta were found both on resting and activated T cells. Cellular activation was shown to result in a five- to sixfold increase in the number of TGF-beta receptors on a per cell basis, without a change in the affinity of the receptor. Finally, the observations that activated T cells produce TGF-beta mRNA and that TGF-beta biologic activity is present in supernatants conditioned by activated T cells is strong evidence that T cells themselves are a source of TGF-beta. Resting T cells were found to have low to undetectable levels of TGF-beta mRNA, while PHA activation resulted in a rapid increase in TGF-beta mRNA levels (within 2 h). Both T4 and T8 lymphocytes were found to make mRNA for TGF-beta upon activation. Using both a soft agar assay and a competitive binding assay, TGF-beta biologic activity was found in supernatants conditioned by T cells; T cell activation resulted in a 10-50-fold increase in TGF-beta production. Thus, TGF-beta may be an important antigen-nonspecific regulator of human T cell proliferation, and important in T cell interaction with other cell types whose cellular functions are modulated by TGF-beta.

scholarly journals The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment

2020 ◽  
Author(s):  
Mohammad H. Rashid ◽  
Thaiz F. Borin ◽  
Roxan Ara ◽  
Raziye Piranlioglu ◽  
Bhagelu R. Achyut ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Cell Types ◽  
Biological Macromolecules

AbstractMyeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.

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