scholarly journals Clonally expanded, GPR15-expressing pathogenic effector TH2 cells are associated with eosinophilic esophagitis

2021 ◽  
Vol 6 (62) ◽  
pp. eabi5586 ◽  
Author(s):  
Duncan M. Morgan ◽  
Bert Ruiter ◽  
Neal P. Smith ◽  
Ang A. Tu ◽  
Brinda Monian ◽  
...  
Keyword(s):  
T Cells ◽  
Eosinophilic Esophagitis ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Specific Population ◽  
Food Antigen ◽  
Esophageal Tissue ◽  
Duodenal Biopsies ◽  
Active Disease

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the recruitment of eosinophils to the esophagus, resulting in chronic inflammation. We sought to understand the cellular populations present in tissue biopsies of patients with EoE and to determine how these populations are altered between active disease and remission. To this end, we analyzed cells obtained from esophageal biopsies, duodenal biopsies, and peripheral blood of patients with EoE diagnosed with active disease or remission with single-cell RNA and T cell receptor (TCR) sequencing. Pathogenic effector TH2 (peTH2) cells present in the esophageal biopsies of patients with active disease expressed distinct gene signatures associated with the synthesis of eicosanoids. The esophageal tissue–resident peTH2 population also exhibited clonal expansion, suggesting antigen-specific activation. Peripheral CRTH2+CD161− and CRTH2+CD161+ memory CD4+ T cells were enriched for either a conventional TH2 phenotype or a peTH2 phenotype, respectively. These cells also exhibited substantial clonal expansion and convergence of TCR sequences, suggesting that they are expanded in response to a defined set of antigens. The esophagus-homing receptor GPR15 was up-regulated by peripheral peTH2 clonotypes that were also detected in the esophagus. Finally, GPR15+ peTH2 cells were enriched among milk-reactive CD4+ T cells in patients with milk-triggered disease, suggesting that these cells are an expanded, food antigen–specific population with enhanced esophagus homing potential.

scholarly journals Massive clonal expansion of polycytotoxic skin and blood CD8+ T cells in patients with toxic epidermal necrolysis

2021 ◽  
Vol 7 (12) ◽  
pp. eabe0013
Author(s):  
Axel Patrice Villani ◽  
Aurore Rozieres ◽  
Benoît Bensaid ◽  
Klara Kristin Eriksson ◽  
Amandine Mosnier ◽  
...  
Keyword(s):  
T Cells ◽  
Toxic Epidermal Necrolysis ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Effector Memory ◽  
Skin Symptoms ◽  
Tcr Repertoire ◽  
Repertoire Sequencing ◽  
Life Threatening ◽  
Cutaneous Adverse Drug Reaction

Toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction. To better understand why skin symptoms are so severe, we conducted a prospective immunophenotyping study on skin and blood. Mass cytometry results confirmed that effector memory polycytotoxic CD8+ T cells (CTLs) are the main leucocytes in TEN blisters at the acute phase. Deep T cell receptor (TCR) repertoire sequencing identified massive expansion of unique CDR3 clonotypes in blister cells. The same clones were highly expanded in patient’s blood, and the degree of their expansion showed significant correlation with disease severity. By transducing α and β chains of the expanded clonotypes into a TCR-defective cell line, we confirmed that those cells were drug specific. Collectively, these results suggest that the relative clonal expansion and phenotype of skin-recruited CTLs condition the clinical presentation of cutaneous adverse drug reactions.

The T-cell receptor Vβgene repertoire and clonal expansion from peripheral blood T cells in benzene-exposed workers in China

Hematology ◽  
2009 ◽  
Vol 14 (2) ◽  
pp. 106-110 ◽  
Author(s):  
Bo Li ◽  
Yangqiu Li ◽  
Shaohua Chen ◽  
Lijian Yang ◽  
Wei Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Exposed Workers

scholarly journals Clonal expansion of CD8+ T cells reflects graft-versus-leukemia activity and precedes durable remission following DLI

2021 ◽  
Author(s):  
Christian R Schultze-Florey ◽  
Leonie Kuhlmann ◽  
Solaiman Raha ◽  
Joana Barros-Martins ◽  
Ivan Odak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Prospective Clinical Study ◽  
Hematopoietic Stem ◽  
Graft Versus Leukemia ◽  
Αβ T Cells ◽  
Durable Remission

Donor lymphocyte infusion (DLI) is a standard of care for relapse of AML after allogeneic hematopoietic stem cell transplantation (aHSCT). Currently it is poorly understood how and when CD8+ αβ T cells exert graft-versus-leukemia (GvL) activity after DLI. Also, there is no reliable biomarker to monitor GvL activity of the infused CD8+ T cells. Therefore, we analyzed the dynamics of CD8+ αβ T cell clones in DLI-patients. In this prospective clinical study of 29 patients, we performed deep T cell receptor β (TRB) sequencing of sorted CD8+ αβ T cells to track patients' repertoire changes in response to DLI. Upon first occurrence of GvL, longitudinal analyses revealed a preferential expansion of distinct CD8+ TRB clones (n=14). This did not occur in samples of patients without signs of GvL (n=11). Importantly, early repertoire changes 15 days after DLI predicted durable remission for the 36 months study follow-up. Furthermore, absence of clonal outgrowth of the CD8+ TRB repertoire after DLI was an early biomarker that predicted relapse at a median time of 11.2 months ahead of actual diagnosis. Additionally, unbiased sample analysis regardless of the clinical outcome revealed that patients with decreasing CD8+ TRB diversity at day 15 after DLI (n=13) had a lower relapse incidence (P=0.0040) compared to patients without clonal expansion (n=6). In conclusion, CD8+ TRB analysis may provide a reliable tool for predicting the efficacy of DLI and holds the potential to identify patients at risk for progression and relapse after DLI.

Specific Cytotoxicity and Clonal Expansion of TCR Vβ Subfamily T Cells Induced by PML-RARα Peptide.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3904-3904
Author(s):  
Yangqiu Li ◽  
Ji Tang ◽  
Lijian Yang ◽  
Shaohua Chen ◽  
Yubing Zhou
Keyword(s):  
T Cells ◽  
Cord Blood ◽  
Mononuclear Cells ◽  
Statistical Significance ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Control Group ◽  
Effector Cells ◽  
Specific Cytotoxicity

Abstract The analysis of T cell receptor (TCR) Vβ repertoire is one of the sensitive methods to identify the clonal expansion T cells which response to tumor associated antigens. Understanding the clonality and restricted usage of TCR Vβ repertoire of expanded T-cells induced by PML-RARα peptide may be useful in helping design the new immunotherapeutic strategy specifically for acute promyelocytic leukemia (APL).The aim of the present study was to investigate the specific cytotoxicity and clonality of TCR Vβ repertoire in cord blood T cells induced by PML-RARα peptide (LSSCITQGKAIETQSSSSEE) in vitro. Cord blood mononuclear cells were amplified by IL-2, anti-CD3 and anti-CD28 antibody with different concentration (16.7μg /ml, 33.3μg /ml or 50μg /ml respectively) of synthetic PML-RARα peptide. The induced T cells were collected at different time points after culture (3, 6, 9, 10, 12 or 15 days). The expression and clonality of TCR Vβ subfamilies within induced T cells were analyzed by using RT-PCR and genescan technique. The cytotoxicity of induced T cells was detected by LDH release assay. The results showed that the best condition for T cells induction and amplication was at a concentration with 16.7μg /ml of PML-RARα peptide and at a culture duration with 10 to 15 day. TCR Vβ repertoire analysis showed that restricted expression and cloanl expansion of TCR Vβ subfamily cord blood T cells could be identified after induction by PML-RARα peptide. Clonal expanded T cells were found in Vβ13, Vβ14 and Vβ16 subfamlies respectively. The induced T cells were showed to have the specific cytotoxicity for NB4 cell line (effector cells: tagerted cells=20:1), the cytotoxicity rates were 49.65±6.7% (p<0.05) at day 10th and 73.13±8.42% (p<0.01) at day 15th after culture, which show statistical significance in compare to the control group (without PML-RARα induction). In conclusions, the PML-RARα peptide could induce the clonal expansion T cells from cord blood in vitro, which may have specific cytotoxicity for PML-RARα+ cells.

scholarly journals Chemokine Receptor Expression Identifies Pre–T Helper (Th)1, Pre–Th2, and Nonpolarized Cells among Human CD4+ Central Memory T Cells

2004 ◽  
Vol 200 (6) ◽  
pp. 725-735 ◽  
Author(s):  
Laura Rivino ◽  
Mara Messi ◽  
David Jarrossay ◽  
Antonio Lanzavecchia ◽  
Federica Sallusto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Memory T Cells ◽  
Cell Receptor ◽  
Central Memory ◽  
Th2 Cells ◽  
T Helper ◽  
Central Memory T Cells ◽  
Th 1

We previously reported that central–memory T cells (TCM cells), which express lymph node homing receptors CCR7 and CD62L, are largely devoid of effector functions but acquire characteristics of effector–memory T cells (TEM cells) (i.e., CCR7− T helper [Th]1 or Th2 cells) after stimulation with T cell receptor agonists or homeostatic cytokines. Here we show that three chemokine receptors identify functional subsets within the human CD4+ TCM cell pool. TCM cells expressing CXCR3 secreted low amounts of interferon γ, whereas CCR4+ TCM cells produced some interleukin (IL)-4, but not IL-5. In response to IL-7 and IL-15, CXCR3+ TCM and CCR4+ TCM cells invariably generated fully differentiated CCR7− Th1 and Th2 cells, respectively, suggesting that they represent pre-Th1 and pre-Th2 cells. Conversely, CXCR5+ TCM cells lacking CXCR3 and CCR4 remained nonpolarized and retained CCR7 and CD62L expression upon cytokine-driven expansion. Unlike naive cells, all memory subsets had a low T cell receptor rearrangement excision circle content, spontaneously incorporated bromodeoxyuridine ex vivo, and contained cells specific for tetanus toxoid. Conversely, recall responses to cytomegalovirus and vaccinia virus were largely restricted to CXCR3+ TCM and TEM cells. We conclude that antigen-specific memory T cells are distributed between TEM cells and different subsets of TCM cells. Our results also explain how the quality of primary T cell responses could be maintained by TCM cells in the absence of antigen.

scholarly journals Immunosuppression byN-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

2013 ◽  
Vol 34 (5) ◽  
pp. 820-831 ◽  
Author(s):  
Sascha Kahlfuß ◽  
Narasimhulu Simma ◽  
Judith Mankiewicz ◽  
Tanima Bose ◽  
Theresa Lowinus ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Neuronal Development ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Effector Cells ◽  
Ifn Γ

N-Methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels that play an important role in neuronal development, plasticity, and excitotoxicity. NMDAR antagonists are neuroprotective in animal models of neuronal diseases, and the NMDAR open-channel blocker memantine is used to treat Alzheimer's disease. In view of the clinical application of these pharmaceuticals and the reported expression of NMDARs in immune cells, we analyzed the drug's effects on T-cell function. NMDAR antagonists inhibited antigen-specific T-cell proliferation and cytotoxicity of T cells and the migration of the cells toward chemokines. These activities correlated with a reduction in T-cell receptor (TCR)-induced Ca2+mobilization and nuclear localization of NFATc1, and they attenuated the activation of Erk1/2 and Akt. In the presence of antagonists, Th1 effector cells produced less interleukin-2 (IL-2) and gamma interferon (IFN-γ), whereas Th2 cells produced more IL-10 and IL-13. However, in NMDAR knockout mice, the presumptive expression of functional NMDARs in wild-type T cells was inconclusive. Instead, inhibition of NMDAR antagonists on the conductivity of Kv1.3 and KCa3.1 potassium channels was found. Hence, NMDAR antagonists are potent immunosuppressants with therapeutic potential in the treatment of immune diseases, but their effects on T cells have to be considered in that Kv1.3 and KCa3.1 channels are their major effectors.

scholarly journals MAIT cell clonal expansion and TCR repertoire shaping in human volunteers challenged with Salmonella Paratyphi A

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Lauren J. Howson ◽  
Giorgio Napolitani ◽  
Dawn Shepherd ◽  
Hemza Ghadbane ◽  
Prathiba Kurupati ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Receptor ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Mait Cells ◽  
Vaccination Strategies ◽  
Human Volunteers ◽  
Tcr Repertoire ◽  
Cell Clonal Expansion ◽  
Mait Cell

Abstract Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)β clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRβ clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes. Our results demonstrate that host exposure to antigen may drive clonal expansion of MAIT cells with increased functional avidity, suggesting a role for specific vaccination strategies to increase the frequency and potency of MAIT cells to optimize effector function.

scholarly journals NSOM/QD-based nanoscale immunofluorescence imaging of antigen-specific T-cell receptor responses during an in vivo clonal Vγ2Vδ2 T-cell expansion

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4220-4232 ◽  
Author(s):  
Yong Chen ◽  
Lingyun Shao ◽  
Zahida Ali ◽  
Jiye Cai ◽  
Zheng W. Chen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Near Field ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Cell Immune Response ◽  
Scanning Optical Microscopy ◽  
Vγ2vδ2 T Cells ◽  
Near Field Scanning

Abstract Nanoscale imaging of an in vivo antigen-specific T-cell immune response has not been reported. Here, the combined near-field scanning optical microscopy– and fluorescent quantum dot–based nanotechnology was used to perform immunofluorescence imaging of antigen-specific T-cell receptor (TCR) response in an in vivo model of clonal T-cell expansion. The near-field scanning optical microscopy/quantum dot system provided a best-optical-resolution (<50 nm) nano-scale imaging of Vγ2Vδ2 TCR on the membrane of nonstimulated Vγ2Vδ2 T cells. Before Ag-induced clonal expansion, these nonstimulating Vγ2Vδ2 TCRs appeared to be distributed differently from their αβ TCR counterparts on the cell surface. Surprisingly, Vγ2Vδ2 TCR nanoclusters not only were formed but also sustained on the membrane during an in vivo clonal expansion of Vγ2Vδ2 T cells after phosphoantigen treatment or phosphoantigen plus mycobacterial infection. The TCR nanoclusters could array to form nanodomains or microdomains on the membrane of clonally expanded Vγ2Vδ2 T cells. Interestingly, expanded Vγ2Vδ2 T cells bearing TCR nanoclusters or nanodomains were able to rerecognize phosphoantigen and to exert better effector function. These studies provided nanoscale insight into the in vivo T-cell immune response.

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