Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness

2006 ◽  
Vol 290 (6) ◽  
pp. L1045-L1051 ◽  
Author(s):  
Naomi Yamashita ◽  
Hiroyuki Tashimo ◽  
Hirofumi Ishida ◽  
Yukiko Matsuo ◽  
Hidekazu Tamauchi ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Bronchial Asthma ◽  
Airway Hyperresponsiveness ◽  
Receptor Gene ◽  
Whole Body ◽  
Th2 Cytokines ◽  
Lipoxygenase Inhibitor ◽  
Airway Responses

The pathophysiological characteristics of bronchial asthma consist of chronic inflammation of airways, airway hyperresponsiveness, and bronchoconstriction. Studies have shown that T helper type 2 (Th2) cytokines produced by both T cells and mast cells in the airway contribute substantially to the initiation of inflammation in both experimental and human bronchial asthma. GATA-3 is a transcription factor essential to the production of Th2 cytokines by T lymphocytes. To clarify the role of GATA-3-expressing T cells in the pathophysiology of bronchial asthma, we utilized transgenic (Tg) mice carrying the GATA-3 gene and the ovalbumin (OVA)-specific T cell receptor gene (GATA-3-Tg/OVA-Tg). Mice were intranasally administrated OVA without systemic immunization. Airway responses were analyzed with noninvasive and invasive whole body plethysmographs. GATA-3-Tg/OVA-Tg mice exhibited significantly higher IL-13 and IL-4 protein expression in the airway. Although there were no differences in the types of infiltrating cells between GATA-3-Tg/OVA-Tg and GATA-3-non-Tg/OVA-Tg mice and no significant increase in IgE level in either group compared with nontreated mice, the response after ACh inhalation was significantly elevated in GATA-3-Tg/OVA-Tg on the seventh day of intranasal treatment with OVA. This hyperresponsiveness was inhibited by 5-lipoxygenase inhibitor and IL-13 neutralization, suggesting that airway responses were induced through IL-13 and leukotriene pathway. In conclusion, airway hyperresponsiveness, a characteristic of bronchial asthma, is regulated at the level of GATA-3 transcription by T lymphocytes in vivo.

scholarly journals Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes

2007 ◽  
Vol 204 (6) ◽  
pp. 1371-1381 ◽  
Author(s):  
Ching-Yu Huang ◽  
Girdhar G. Sharma ◽  
Laura M. Walker ◽  
Craig H. Bassing ◽  
Tej K. Pandita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Receptor ◽  
Receptor Gene ◽  
Cell Receptor ◽  
Cell Compartment ◽  
Joint Formation ◽  
B And T Lymphocytes

Ataxia-telangiectasia mutated (ATM)–deficient lymphocytes exhibit defects in coding joint formation during V(D)J recombination in vitro. Similar defects in vivo should affect both T and B cell development, yet the lymphoid phenotypes of ATM deficiency are more pronounced in the T cell compartment. In this regard, ATM-deficient mice exhibit a preferential T lymphopenia and have an increased incidence of nontransformed and transformed T cells with T cell receptor α/δ locus translocations. We demonstrate that there is an increase in the accumulation of unrepaired coding ends during different steps of antigen receptor gene assembly at both the immunoglobulin and T cell receptor loci in developing ATM-deficient B and T lymphocytes. Furthermore, we show that the frequency of ATM-deficient αβ T cells with translocations involving the T cell receptor α/δ locus is directly related to the number of T cell receptor α rearrangements that these cells can make during development. Collectively, these findings demonstrate that ATM deficiency leads to broad defects in coding joint formation in developing B and T lymphocytes in vivo, and they provide a potential molecular explanation as to why the developmental impact of these defects could be more pronounced in the T cell compartment.

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 IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

scholarly journals Vγ9Vδ2 T cells as a promising innovative tool for immunotherapy of hematologic malignancies

2011 ◽  
Vol 4 (4) ◽  
pp. 211
Author(s):  
Serena Meraviglia ◽  
Carmela La Mendola ◽  
Valentina Orlando ◽  
Francesco Scarpa ◽  
Giuseppe Cicero ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Hematologic Malignancies ◽  
Cytolytic Activity ◽  
Cell Therapies ◽  
Stressed Cells

The potent anti-tumor activities of γδ T cells, their ability to produce pro-inflammatory cytokines, and their strong cytolytic activity have prompted the development of protocols in which γδ agonists or ex vivo-expanded γδ cells are administered to tumor patients. γδ T cells can be selectively activated by either synthetic phosphoantigens or by drugs that enhance their accumulation into stressed cells as aminobisphosphonates, thus offering new avenues for the development of γδ T cell-based immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate the endogenous phosphoantigens, has enabled the investigators to design the experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of the direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen- or aminobisphosphonate-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances in the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel and highly innovative immunotherapy in patients with hematologic malignancies.<br />

Abstract 14366: T-lymphocytes May Contribute to Thrombus Formation in Patients With Acute Coronary Syndrome via Expression of Tissue Factor

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Giovanni Cimmino ◽  
Giovanni Ciccarelli ◽  
Stefano Conte ◽  
Grazia Pellegrino ◽  
Luigi Insabato ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Tissue Factor ◽  
Thrombus Formation ◽  
Specific Antigen ◽  
Activated T Cells ◽  
Coronary Syndrome ◽  
Stable Cad

Background: Activation of T-cells plays an important role in the pathophysiology of acute coronary syndromes (ACS). We have previously shown that plaques from ACS patients are characterized by a selective oligoclonal expansion of T-cells, indicating a specific, antigen-mediated recruitment of T-cells within the unstable lesions. We have also previously reported that activated T-cells in vitro express functional Tissue Factor (TF) on their surface. At the moment, however it is not known whether expression of TF by T-cells may contribute to thrombus formation in vivo. Methods: Blood was collected from the aorta and the coronary sinus of 13 NSTEMI and 10 stable CAD patients. CD3+ cells were selectively isolated and TF gene expression (real time PCR)and protein levels (western blot) were evaluated. In additional 7 STEMI patients, thrombotic formation material was obtained from the occluded coronary artery by catheter aspiration during primary PCI. TF expression in CD3+ cells was evaluated by immunohistochemistry and confocal microscopy. Results: Transcardiac TF expression in CD3+ cells was significantly higher in NSTEMI patients as compared to CD3+ cells obtained from stable CAD patients. Interestingly, thrombi aspirated from STEMI patients resulted enriched in CD3+cells, which expressed TF on their surface as shown in the figure. Conclusions: Our data demonstrate that in patients with ACS, T-lymphocytes may express surface TF, thus contributing to the process of thrombus formation. This finding may shed new light into the pathophysiologyof ACS.

scholarly journals Effects of Thymus vulgaris L., Cinnamomum verum J.Presl and Cymbopogon nardus (L.) Rendle Essential Oils in the Endotoxin-induced Acute Airway Inflammation Mouse Model

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3553
Author(s):  
Eszter Csikós ◽  
Kata Csekő ◽  
Amir Reza Ashraf ◽  
Ágnes Kemény ◽  
László Kereskai ◽  
...  
Keyword(s):  
Mouse Model ◽  
Essential Oils ◽  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Whole Body ◽  
Gas Chromatography Mass Spectrometry ◽  
Thymus Vulgaris ◽  
Inflammatory Conditions ◽  
Inflammatory Parameters

Thyme (TO), cinnamon (CO), and Ceylon type lemongrass (LO) essential oils (EOs) are commonly used for inhalation. However, their effects and mechanisms on inflammatory processes are not well-documented, and the number of in vivo data that would be important to determine their potential benefits or risks is low. Therefore, we analyzed the chemical composition and investigated the activity of TO, CO, and LO on airway functions and inflammatory parameters in an acute pneumonitis mouse model. The components of commercially available EOs were measured by gas chromatography–mass spectrometry. Airway inflammation was induced by intratracheal endotoxin administration in mice. EOs were inhaled during the experiments. Airway function and hyperresponsiveness were determined by unrestrained whole-body plethysmography on conscious animals. Myeloperoxidase (MPO) activity was measured by spectrophotometry from lung tissue homogenates, from which semiquantitative histopathological scores were assessed. The main components of TO, CO, and LO were thymol, cinnamaldehyde, and citronellal, respectively. We provide here the first evidence that TO and CO reduce inflammatory airway hyperresponsiveness and certain cellular inflammatory parameters, so they can potentially be considered as adjuvant treatments in respiratory inflammatory conditions. In contrast, Ceylon type LO inhalation might have an irritant effect (e.g., increased airway hyperresponsiveness and MPO activity) on the inflamed airways, and therefore should be avoided.

Telomerase levels control the lifespan of human T lymphocytes

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 849-857 ◽  
Author(s):  
Alexander Röth ◽  
Hans Yssel ◽  
Jérôme Pène ◽  
Elizabeth A. Chavez ◽  
Mike Schertzer ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Ectopic Expression ◽  
Dominant Negative ◽  
Major Influence ◽  
Telomeric Dna ◽  
Human Telomerase Reverse Transcriptase ◽  
Human T Lymphocytes ◽  
Human T Cells

Abstract The loss of telomeric DNA with each cell division contributes to the limited replicative lifespan of human T lymphocytes. Although telomerase is transiently expressed in T lymphocytes upon activation, it is insufficient to confer immortality. We have previously shown that immortalization of human CD8+ T lymphocytes can be achieved by ectopic expression of the human telomerase reverse transcriptase (hTERT) gene, which encodes for the catalytic component of the telomerase complex. To study the role of endogenous hTERT in the lifespan of human T cells, we blocked endogenous hTERT expression by ectopic expression of dominant-negative (DN) hTERT. Cells expressing DN-hTERT had a decreased lifespan and showed cytogenetic abnormalities, including chromosome ends without detectable telomeric DNA as well as chromosome fusions. These results indicate that while endogenous hTERT cannot prevent overall telomere shortening, it has a major influence on the longevity of human T cells. Furthermore, we show that up-regulation of hTERT in T cells upon activation decreases over time in culture. Long-term–cultured T cells also show a decreased expression of c-myc upon activation, resulting in less c-myc–induced transcription of hTERT. Moreover, memory T cells, which have expanded in vivo upon antigen encounter, expressed a lower level of hTERT upon activation than naive cells from the same donor. The observed inverse correlation between telomerase levels and replicative history suggests that telomerase levels in T cells are limiting and increasingly insufficient to sustain their proliferation.

Perforin-dependent apoptosis functionally compensates Fas deficiency in activation-induced cell death of human T lymphocytes

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4285-4292 ◽  
Author(s):  
Véronique Mateo ◽  
Michael Ménager ◽  
Geneviève de Saint-Basile ◽  
Marie-Claude Stolzenberg ◽  
Bertrand Roquelaure ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Lymphocytes ◽  
Peripheral Tolerance ◽  
Gene Encoding ◽  
Activation Induced Cell Death ◽  
Dependent Cell ◽  
Lymphoproliferative Syndrome ◽  
Dependent Pathway

Activation-induced cell death (AICD) is involved in peripheral tolerance by controlling the expansion of repeatedly stimulated T cells via an apoptotic Fas (CD95; APO-1)–dependent pathway. The TNFRSF-6 gene encoding Fas is mutated in children suffering from autoimmune lymphoproliferative syndrome (ALPS), which is characterized by lymphoproliferation and autoimmunity. We examined AICD in Fas-deficient T cells from ALPS patients. We showed that primary activated Fas-deficient T cells die by apoptosis after repeated T cell antigen receptor (TCR) stimulation despite resistance to Fas-mediated cell death. This Fas-independent AICD was found to be mediated through a cytotoxic granules-dependent pathway. Cytotoxic granules-mediated AICD was also detected in normal T lymphocytes though to a lesser extent. As expected, the cytotoxic granules-dependent AICD was abolished in T cells from Rab27a- or perforin-deficient patients who exhibited defective granules-dependent cytotoxicity. Supporting an in vivo relevance of the cytotoxic granules-dependent AICD in ALPS patients, we detected an increased number of circulating T lymphocytes expressing granzymes A and B. Altogether, these data indicated that the cytotoxic granules-dependent cell death in ALPS may compensate for Fas deficiency in T lymphocytes. Furthermore, they identified a novel AICD pathway as a unique alternative to Fas apoptosis in human peripheral T lymphocytes.

Autoimmune disorder phenotypes in Hvcn1-deficient mice

2013 ◽  
Vol 450 (2) ◽  
pp. 295-301 ◽  
Author(s):  
Mari Sasaki ◽  
Akihiro Tojo ◽  
Yoshifumi Okochi ◽  
Nana Miyawaki ◽  
Daisuke Kamimura ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disorder ◽  
Whole Body ◽  
Activated T Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
In The Wild ◽  
Body Level ◽  
Deficient Mice

Hv channels (voltage-gated proton channels) are expressed in blood cells, microglia and some types of epithelial cells. In neutrophils Hv channels regulate the production of reactive oxygen species through regulation of membrane potential and intracellular pH. Hv channels have also been suggested to play a role in sperm physiology in the human. However, the functions of the Hv channel at the whole-body level are not fully understood. In the present paper we show that Hvcn1 (voltage-gated hydrogen channel 1)-knockout mice show splenomegaly, autoantibodies and nephritis, that are reminiscent of human autoimmune diseases phenotypes. The number of activated T-cells was larger in Hvcn1-deficient mice than in the wild-type mice. Upon viral infection this was remarkably enhanced in Hvcn1-deficient mice. The production of superoxide anion in T-cells upon stimulation with PMA was significantly attenuated in the Hvcn1-deficient mice. These results suggest that Hv channels regulate T-cell homoeostasis in vivo.

Cyclophosphamide induces type I interferon and augments the number of CD44hi T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2024-2030 ◽  
Author(s):  
Giovanna Schiavoni ◽  
Fabrizio Mattei ◽  
Tiziana Di Pucchio ◽  
Stefano M. Santini ◽  
Laura Bracci ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Adoptive Immunotherapy ◽  
Messenger Rna ◽  
Type I ◽  
Type I Ifn ◽  
Term Survival ◽  
Spleen Lymphocytes

Abstract In a previous study, we reported that a single injection of cyclophosphamide (CTX) in tumor-bearing mice resulted in tumor eradication when the animals were subsequently injected with tumor-sensitized lymphocytes. Notably, CTX acted by inducing bystander effects on T cells, and the response to the combined CTX/adoptive immunotherapy regimen was inhibited in mice treated with antibodies to mouse interferon (IFN)–/β. In the present study, we have investigated whether CTX induced the expression of type I IFN, and we have characterized the CTX effects on the phenotype of T cells in normal mice. CTX injection resulted in an accumulation of type I IFN messenger RNA in the spleen of inoculated mice, at 24 to 48 hours, that was associated with IFN detection in the majority of the animals. CTX also enhanced the expression of the Ly-6C on spleen lymphocytes. This enhancement was inhibited in mice treated with anti–type I IFN antibodies. Moreover, CTX induced a long-lasting increase in in vivo lymphocyte proliferation and in the percentage of CD44hiCD4+ and CD44hiCD8+T lymphocytes. These results demonstrate that CTX is an inducer of type I IFN in vivo and enhances the number of T cells exhibiting the CD44hi memory phenotype. Since type I IFN has been recently recognized as the important cytokine for the in vivo expansion and long-term survival of memory T cells, we suggest that induction of this cytokine may explain at least part of the immunomodulatory effects observed after CTX treatment. Finally, these findings provide a new rationale for combined treatments with CTX and adoptive immunotherapy in cancer patients.

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