scholarly journals IL-4-induced hysteresis in naïve T cell activation

2020 ◽  
Author(s):  
Alexandre P. Meli ◽  
Yaqiu Wang ◽  
Dimitri A. de Kouchkovsky ◽  
Yong Kong ◽  
Malay K. Basu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Helminth Infection ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Naïve T Cell ◽  
Naive T Cell

AbstractNaïve T cells are generally considered to be a homogeneous population, but for their unique T cell receptors (TCRs). Naïve T cells are activated within a specific cytokine milieu upon interaction with antigen-presenting cells through cognate TCR::MHC-peptide interaction and co-stimulation. Here we demonstrate that naïve T cells are transcriptionally heterogeneous, and that the relative proportions of transcriptionally distinct naïve T cell subpopulations are modified by immune responses, such as during helminth infection. Not only are cognate naïve T cells activated during an immune response, but the cytokine produced - such as IL-4 during helminth infection - changes the transcriptome of bystander naïve T cells. Such changes in gene expression and population level heterogeneity in bystander naïve T cells result in altered responses to a concurrent immune challenge, for instance, hypo-responsiveness to vaccination. Thus, naïve T cell activation is not the result of a singular temporal event, but is characterized by hysteresis. Our studies suggest that antigen-agnostic, cytokine-dependent naïve T cell conditioning and resulting hysteresis is a mechanism that integrates input signals from concurrent infections for the regulation of the overall magnitude of the immune response.

scholarly journals VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

Science ◽  
2020 ◽  
Vol 367 (6475) ◽  
pp. eaay0524 ◽  
Author(s):  
Mohamed A. ElTanbouly ◽  
Yanding Zhao ◽  
Elizabeth Nowak ◽  
Jiannan Li ◽  
Evelien Schaafsma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Subset ◽  
Peripheral Tolerance ◽  
Cell Immune Response ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Naïve T Cell ◽  
Naive T Cell

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

scholarly journals Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice

2018 ◽  
Vol 115 (52) ◽  
pp. 13347-13352 ◽  
Author(s):  
Noga Ron-Harel ◽  
Giulia Notarangelo ◽  
Jonathan M. Ghergurovich ◽  
Joao A. Paulo ◽  
Peter T. Sage ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Carbon Metabolism ◽  
Cell Activation ◽  
Aged Mice ◽  
Naïve T Cells ◽  
One Carbon Metabolism ◽  
Naïve T Cell ◽  
Naive T Cell

T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation. We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.

scholarly journals Antigen-independent activation of naive and memory resting T cells by a cytokine combination.

1994 ◽  
Vol 180 (3) ◽  
pp. 1159-1164 ◽  
Author(s):  
D Unutmaz ◽  
P Pileri ◽  
S Abrignani
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Effector Function ◽  
Necrosis Factor Alpha ◽  
Naive T Cells ◽  
Naïve T Cells

We investigated whether human resting T cells could be activated to proliferate and display effector function in the absence of T cell receptor occupancy. We report that combination of interleukin 2 (IL-2), tumor necrosis factor alpha, and IL-6 activated highly purified naive (CD45RA+) and memory (CD45RO+) resting CD4+ T cells to proliferate. Under this condition, memory resting T cells could also display effector function as measured by lymphokine synthesis and help for immunoglobulin production by B cells. This novel Ag-independent pathway of T cell activation may play an important role in vivo in recruiting effector T cells at the site of immune response and in maintaining the clonal size of memory T cells in the absence of antigenic stimulation. Moreover, cytokines can induce proliferation of naive T cells without switch to memory phenotype and this may help the maintenance of the peripheral pool of naive T cells.

scholarly journals Role of T-cell activation in salt-sensitive hypertension

2019 ◽  
Vol 316 (6) ◽  
pp. H1345-H1353 ◽  
Author(s):  
Jiafa Ren ◽  
Steven D. Crowley
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
T Subsets ◽  
Underlying Mechanisms ◽  
Salt Sensitive Hypertension

The contributions of T lymphocytes to the pathogenesis of salt-sensitive hypertension has been well established. Under hypertensive stimuli, naive T cells develop into different subsets, including Th1, Th2, Th17, Treg, and cytotoxic CD8+ T cells, depending on the surrounding microenviroment in organs. Distinct subsets of T cells may play totally different roles in tissue damage and hypertension. The underlying mechanisms by which hypertensive stimuli activate naive T cells involve many events and different organs, such as neoantigen presentation by dendritic cells, high salt concentration, and the milieu of oxidative stress in the kidney and vasculature. Infiltrating and activated T subsets in injured organs, in turn, exert considerable impacts on tissue dysfunction, including sodium retention in the kidney, vascular stiffness, and remodeling in the vasculature. Therefore, a thorough knowledge of T-cell actions in hypertension may provide novel insights into the development of new therapeutic strategies for patients with hypertension.

Interleukin-7–treated naive T cells can be productively infected by T-cell–adapted and primary isolates of human immunodeficiency virus 1

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3310-3318 ◽  
Author(s):  
Carolyn M. Steffens ◽  
Elizabeth Z. Managlia ◽  
Alan Landay ◽  
Lena Al-Harthi
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Productive Infection ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Interleukin 7 ◽  
Immunodeficiency Virus ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract Although human immunodeficiency virus (HIV)gag/pol DNA can be detected in naive T cells, whether naive T cells can be productively infected by HIV is still questionable. Given that interleukin-7 (IL-7) is a prospective therapeutic immunomodulator for the treatment of HIV, we evaluated the effect of IL-7 on promoting naive T-cell infection of laboratory-adapted (IIIB), M-tropic, and primary isolates of HIV. Initially, we determined that the 3 cell surface markers widely used to identify naive T cells (CD45RA+CD45RO−, CD45RA+CD62L+, and CD45RO−CD27+CD95low) are all equivalent in T-cell receptor excision circle content, a marker for the replicative history of a cell as well as for de novo T cells. We therefore used CD45RA+CD45RO− expression to define naive T cells in this study. We demonstrate that although untreated or IL-2–treated naive T cells are not productively infected by HIV, IL-7 pretreatment mediated the productive infection of laboratory-adapted, M-tropic, and primary isolates of HIV as determined by p24 core antigen production. This up-regulation was between 8- and 58-fold, depending on the HIV isolate used. IL-7 pretreatment of naive T cells also potently up-regulated surface expression of CXCR4 but not CCR5 and mediated the expansion of naive T cells without the acquisition of the primed CD45RO phenotype. Collectively, these data indicate that IL-7 augments naive T-cell susceptibility to HIV and that under the appropriate environmental milieu, naive T cells may be a source of HIV productive infection. This information needs to be considered in evaluating IL-7 as an immunomodulator for HIV-infected patients.

scholarly journals Frequencies of FoxP3+ naïve T cells are related to both viral load and naïve T cell proliferation responses in HIV disease

2011 ◽  
Vol 90 (3) ◽  
pp. 621-628 ◽  
Author(s):  
Benigno Rodriguez ◽  
Douglas A. Bazdar ◽  
Nicholas Funderburg ◽  
Robert Asaad ◽  
Angel A. Luciano ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
T Cell Proliferation ◽  
Hiv Disease ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Naïve T Cell ◽  
Naive T Cell

scholarly journals Allogeneic T Cells Utilize Glycolysis As the Predominant Metabolic Pathway to Induce Acute Graft-Versus-Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2419-2419
Author(s):  
Hung Nguyen ◽  
Kelley MK Haarberg ◽  
Yongxia Wu ◽  
Jianing Fu ◽  
Jessica Lauren Heinrichs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Metabolic Process ◽  
Naive T Cells ◽  
Graft Versus Host ◽  
Naïve T Cells

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapy for hematologic malignancies through T cell-mediated graft-versus-leukemia (GVL) effects, but allogeneic T cells often lead to severe graft-versus-host disease (GVHD). Cell metabolism plays pivotal roles in T-cell activation, differentiation, and function. However, understanding of T cell-metabolism is still superficial, and even less is known how metabolism regulates T-cell response to alloantigens and GVHD induction after allo-HCT. In this study, using a high-throughput liquid-and gas-chromatography-based metabolic approach, we compared the metabolic process of allogeneic versus syngeneic T cells at day 4 (early preclinical stage), day 7 (preclinical stage), and day 14 (clinical stage) post bone marrow transplantation (BMT), with naïve T cells as additional controls. Over 180 metabolites were identified and quantified. T cells after being transferred into pre-conditioned recipients were undergoing metabolic reprogramming reflected by attenuated levels of metabolites involving anabolic pathways of lipids, amino acids, nucleotides and carbohydrates in allogeneic and syngeneic T cells compared to those in naïve T cells. In comparison with syngeneic T cells, allogeneic T cells exhibited increased oxidative stress, reflected by higher levels of eicosanoid, cyclooxygenase, and lipoxygenase-oxidized eicosanoids, and decreased levels of antioxidant compounds such as glutathione (GSH) and glutathione disulfide (GSSG). To obtain biomass for robust proliferation followed by alloantigen stimulation, allogeneic T cells further increased pentose phosphate and polyamine synthesis by day 7 post-BMT. We also observed that allogeneic T cells and syngeneic T cells expressed comparable levels of metabolites in fatty acid and glutamine oxidized in tricarboxylic acid (TCA) cycle, which was much lower than those of naïve T cells. Importantly, allogeneic T cells exhibited higher levels of metabolites in glycolysis as compared to syngeneic T cells regardless of time points. Consistently, using Seahorse approach, we also found that allogeneic T cells significantly increased aerobic glycolysis as compared to syngeneic T cells post-BMT, whereas oxidative phosphorylation was similar. Moreover, blocking glycolysis with 2-deoxyglucose remarkably inhibited donor T-cell proliferation, expansion and Th1 differentiation after allo-BMT. Thus, aerobic glycolysis rather than mitochondrial oxidative phosphorylation is the preferential metabolic process required for the optimal expansion and activation of allogeneic T cells. Given mechanistic target of rapamycin (mTOR) plays an essential role in controlling T-cell metabolism particularly in glycolysis, we hypothesized that targeting mTOR would prevent GVHD by inhibiting glycolytic metabolism. Using pharmacological and genetic approaches, we unequivocally demonstrated that mTOR, especially mTORC1, was essential for T-cell glycolytic activity and for GVHD induction. Mechanistically, mTORC1 promoted T-cell activation, expansion, Th1 differentiation, and migration into GVHD target organs, but inhibited the generation of induced T regulatory cells. In conclusion, the current work provides compelling evidence that allogeneic T cells utilize glycolysis as a predominant metabolic process after BMT. Furthermore, we validate glycolysis or its key regulator, such as mTORC1, to be a valid therapeutic target for the control of GVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Blinatumomab-Induced T Cell Activation at Single Cell Transcriptome Resolution

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3886-3886
Author(s):  
Hong Yin ◽  
Yi Huo ◽  
Zhen Sheng ◽  
Chi-Ming Li ◽  
Daniel C Ellwanger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Target Cells ◽  
Ex Vivo Model ◽  
Naive T Cells ◽  
Naïve T Cells

Introduction Blinatumomab, a bi-specific T cell engager (BiTE®) combining the VH and VL domains of two antibodies against human CD19 and CD3, has been approved by U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed or refractory B precursor ALL (r/r B-ALL) for its clinical benefit demonstrated in different clinical trials. Clinical trials have also shown that there are still patients refractory to blinatumomab. It is thus important to understand the resistance mechanisms. Blinatumomab connects patients' autologous T cells and target cells to form immunologic synapse which potently triggers the activation signaling cascades in T cells and guides T cells to recognize and induce perforin/granzyme-mediated lysis of CD19+ B-ALL cells. Previous studies showed blinatumomab-mediated cytotoxicity involves different T cell subpopulations. But response of each T cell subpopulation to blinatumomab treatment remained largely unknown. Methods and Results In this study, we used 10X Genomics based single cell RNA sequencing to analyze the transcriptome of single T cells before and after blinatumomab treatment. First, ex vivo blinatumomab cytotoxicity model was established, in which healthy PBMCs were used as effector cells and cocultured with target cells (RS4;11 cells or SUP-B15 cells) at an effector-to-target cell ratio of 10:1 with 0.1 ng/mL blinatumomab. Then, PBMCs and BMMCs from 2 B-ALL patients were cultured with 10 ng/mL blinatumomab. Cells from both ex vivo model and patient samples were sequenced using 10X Genomics platform. In total, transcriptome of 17920 single T cells from the ex vivo model and 2271 single T cells from patient sample were analyzed. Based on T cell trajectory analysis, we identified four distinct populations of blinatumomab-activated T cells, which were derived from CD8+ effector memory T (TEM) cells, CD4+ central memory (TCM) cells, naïve T cells and Tregs, respectively. The differentially expressed genes in activated clusters were analyzed to reflect T cell activation mechanisms. The result showed blinatumomab induced the upregulation of aerobic glycolysis pathway (PKM, PGAM1, ENO1, GAPDH and LDHA), cytoskeleton dynamics pathway (ACTD1, ACTB, NME1 and TUBA1B), IFN-responsive pathway (GBP1, PSME2, WARS, CXCL10 and STAT1), and the upregulation of well-known immune-related genes (TNFRSF4, TNFRSF18, LAG3, CD69, IL2RA, MIR155HG, BATF, SH2D2A, LTA, NFKBIA and NDFIP2). We found blinatumomab-activated CD8+ TEM cells showed stronger cytotoxic capability than other activated populations with specific production of cytotoxic factors (PRF1, IFNG and FASLG) and cytokines (CCL2, CCL3, CCL3L1, CCL4, CCL4L2, CCL8, XCL1, XCL2, TNFSF9 and TNFSF14). Last, differential gene expression analysis revealed that co-stimulatory (TNFRSF4,TNFRSF9 and TNFRSF18) and co-inhibitory receptors (LAG3 and TIGIT) were similarly up-regulated in clusters activated from memory and naïve T cells, indicating ligand dependent T cell functional outcomes induced by blinatumomab. Conclusion In summary, we used single cell sequencing to map the blinatumomab-mediated T cell activation state transition and reveal the molecular changes in different T cell subpopulations. Memory T cells, naïve T cells and Tregs were identified functional populations after blinatumomab treatment. CD8+ TEM accounted for the majority of blinatumomab-induced cytotoxicity. Furthermore, T cell co-regulatory receptors were identified as potential targets accountable for blinatumomab sensitivity or resistance mechanisms. The study demonstrated that the collected cellular transcriptional profiles can serve as resource to explore novel strategies to enhance the efficacy of blinatumomab. Disclosures Yin: Amgen: Employment. Huo:Amgen: Employment. Sheng:Amgen: Employment. Li:Amgen: Employment. Ellwanger:Amgen: Employment. Lu:Amgen: Employment. Homann:Amgen: Employment. Wang:Amgen: Employment. Ren:Ruijin hospital: Employment.

Engineering Mesenchymal Cells with Interleukin 7 Gene: In Vitro Effects on Naive T Cell Population.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5135-5135
Author(s):  
Paolo Sportoletti ◽  
Beatrice Del Papa ◽  
Mariangela De Ioanni ◽  
Lorenzo Moretti ◽  
Elisabetta Bonifacio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Mesenchymal Cells ◽  
Independent Effect ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Interleukin 7 ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract T cell homeostasis is regulated by several molecules among which Interleukin 7 (IL-7) plays an essential role for survival and homeostatic proliferation of peripheral naive T cells. In a previous study we demonstrated whether human mesenchymal cells could be engineered with IL-7 gene to produce functional level of this cytokine. Now we analysed the impact of different quantities of IL-7 produced by mesenchymal cells on survival and proliferation of a negative immunoselected naive (CD3+/CD45RA+) T cell population. Co-cultivation of peripheral naive T cells with mesenchymal cells producing low (16 pg/ml) or high (1000 pg/ml) IL-7 levels or in presence of exogenous IL-7 (0,01 ng/ml and 100 ng/ml) maintained the CD3+/CD45RA+ naive T cell phenotype. The chemokine receptor CCR7+ expression was also maintained among this T cell population. Naive T cell molecular characteristics were maintained as assessed by the Vβ spectratyping complexity score which shows the maintenance of a broad T cell repertoire. No Th1 or Th2 differentiation was observed as assessed by IFNγ or IL-4 accumulation. In contrast only mesenchymal cells producing high IL-7 amount caused increases in the activation (CD25 31.2%±12 vs 10%±3.5, p<0.05), proliferation (CD71 17.8±7% vs 9.3%±3, p<0.05), apoptosis (assessed by annexin V: 18.6%±5 vs 14.9%±2.6, p>0.05) and phase S cell cycle (15% vs 6.9%, p>0.05). Exogenous IL-7 did not exert any significant effect. In conclusion, we demonstrated that IL-7 produced by mesenchymal cells has a dose-independent effect on naive T cell survival while exerts a dose-dependent effect on activation/proliferation. Due to continuous production of IL-7 by engineered cells, our system emerge as more efficacious than the exogenous IL-7.

Generating Chimeric Antigen Receptors Utilizing Novel Anti-CD3 Nanobeads

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5949-5949
Author(s):  
Liora M. Schultz ◽  
Debra K Czerwinski ◽  
Aihua Fu ◽  
Shoshana Levy ◽  
Ronald Levy
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Receptors ◽  
Chimeric Antigen Receptors ◽  
Car T Cell ◽  
Car T ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract The processes of ex vivo transduction of T cells to express chimeric antigen receptors (CARs) and of CAR+ T cell expansion influence the phenotype, function and ultimate fate of the final CAR+T cell product infused into patients. CAR constructs, despite expression of endogenous activation signals, require exogenous T cell activation during CAR transduction to allow optimal lenti-viral or retroviral-mediated integration of the CAR gene of interest into T cells. Clinical CAR therapy trials utilize anti-CD3 antibody-mediated activation or combined CD3 and CD28 stimulation using CD3, CD28 specific magnetic beads. We introduce novel magnetic nanoparticle beads generated from iron oxide nanoparticles conjugated to streptavidin and bound to biotinylated T cell activating antibodies for the purpose of CAR transduction. The small size of these nanobeads confers the advantage of decreased steric hindrance and enhanced capability of bead surface antibodies to access T cell surface antigen for binding and stimulation. We achieve efficient CAR transduction using anti-CD3 nanobead-mediated T cell stimulation and demonstrate CD19 specific CAR-mediated cytotoxicity of CD19+ tumor using an annexin V and 7AAD cytotoxicity assay. Evaluation of T cell phenotype following anti-CD3 nanobead-mediated T cell activation demonstrates preferential activation of naïve T cells as compared to central and effector memory cells. Addition of anti-CD28 costimulation is not necessary to achieving or inhibiting this preferential naïve T cell activation. Naïve T cells exhibit greater replicative capacity and anti-tumor function as compared to both effector and central memory T cells for adoptive transfer. We anticipate that preferential generation of naïve T cell derived CAR+ T cells achieved by introducing anti-CD3 nanobead stimulation can further improve the outcomes of clinical trials using CAR therapy. Disclosures Fu: NVIGEN Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

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