scholarly journals Decreased Frequencies of Gamma/Delta T Cells Expressing Th1/Th17 Cytokine, Cytotoxic, and Immune Markers in Latent Tuberculosis-Diabetes/Pre-Diabetes Comorbidity

2021 ◽  
Vol 11 ◽  
Author(s):  
Gokul Raj Kathamuthu ◽  
Nathella Pavan Kumar ◽  
Kadar Moideen ◽  
Pradeep A. Menon ◽  
Subash Babu
Keyword(s):  
T Cells ◽  
Latent Tuberculosis ◽  
Γδ T Cells ◽  
Positive Control ◽  
Gamma Delta ◽  
Immune Markers ◽  
Antigen Stimulation ◽  
Significant Difference ◽  
Control Antigen ◽  
Th17 Cytokine

Antigen-specific gamma-delta (γδ) T cells are important in exhibiting anti-mycobacterial immunity, but their role in latent tuberculosis (LTB) with diabetes mellitus (DM) or pre-DM (PDM) and non-DM comorbidities have not been studied. Thus, we have studied the baseline, mycobacterial (PPD, WCL), and positive control antigen-stimulated γδ T cells expressing Th1 (IFNγ, TNFα, IL-2) and Th17 (IL-17A, IL-17F, IL-22) cytokine as well as cytotoxic (perforin [PFN], granzyme [GZE B], granulysin [GNLSN]) and immune (GMCSF, PD-1, CD69) markers in LTB (DM, PDM, NDM) comorbidities by flow cytometry. In the unstimulated (UNS) condition, we did not observe any significant difference in the frequencies of γδ T cells expressing Th1 and Th17 cytokine, cytotoxic, and immune markers. In contrast, upon PPD antigen stimulation, the frequencies of γδ T cells expressing Th1 (IFNγ, TNFα) and Th17 (IL-17F, IL-22) cytokine, cytotoxic (PFN, GZE B, GNLSN), and immune (CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Similarly, upon WCL antigen stimulation, the frequencies of γδ T cells expressing Th1 (TNFα) and Th17 (IL-17A, IL-22) cytokine, cytotoxic (PFN), and immune (PD-1, CD69) markers were significantly diminished in LTB DM and/or PDM individuals compared to LTB NDM individuals. Finally, upon P/I stimulation we did not observe any significant difference in the γδ T cell frequencies expressing cytokine, cytotoxic, and immune markers between the study populations. The culture supernatant levels of IFNγ, TNFα, and IL-17A cytokines were significantly increased in LTB DM and PDM after stimulation with Mtb antigens compared to LTB NDM individuals. Therefore, diminished γδ T cells expressing cytokine, cytotoxic, and other immune markers and elevated levels of cytokines in the supernatants is a characteristic feature of LTB PDM/DM co-morbidities.

scholarly journals Alterations in Gamma-Delta T Cells in Patients With Primary Biliary Cholangitis

2021 ◽  
Author(s):  
Sha Chen ◽  
Tingting Lv ◽  
Guangyong Sun ◽  
Shuxiang Li ◽  
Weijia Duan ◽  
...  
Keyword(s):  
T Cells ◽  
Flow Cytometric Analysis ◽  
Γδ T Cells ◽  
Absolute Number ◽  
Primary Biliary Cholangitis ◽  
Gamma Delta ◽  
Potential Marker ◽  
Hla Dr ◽  
Tnf Α ◽  
Elevated Expression

Abstract Background & Aims Gamma-delta (γδ) T cells are involved in the development of diverse liver and autoimmune diseases, whereas the role of γδ T cells in primary biliary cholangitis (PBC) remains unclear. Methods We analyzed the number, phenotypes, and functional molecules of γδ T cells in PBC patients (n = 74) and sex- and age-matched healthy controls (HCs) (n = 74) by flow cytometric analysis. Results We identified two distinct functional subsets of circulating γδ T cells according to the CD3/TCRγδ complex: the TCRγδhigh and TCRγδlow subsets. Approximately three-quarters of cells in the TCRγδhigh subset were Vδ1 T cells, while Vδ2 T cells were enriched in the TCRγδlow subset in HCs. The frequency and absolute number of circulating TCRγδlow cells was significantly decreased in PBC patients compared with HCs (p < 0.001). Furthermore, the frequency of TCRγδlow cells was negatively correlated with disease severity and positively correlated with the ursodeoxycholic acid response. TCRγδlow cells exhibited a similar apoptotic and proliferative phenotype but enhanced liver-homing chemokine receptor (CXCR6) expression in PBC patients compared with HCs. In addition, both TCRγδhigh and TCRγδlow subsets were more activated in PBC compared with HCs, characterized by elevated expression levels of CD69 and HLA-DR. Finally, we found an increased granzyme B (GZMB) production and similar IFN-γ and TNF-α production of TCRγδlow cells in PBC patients compared with HCs. Conclusion The TCRγδlow subset might be a potential marker for disease progression and treatment response in PBC, which may play a crucial role in liver injury through increased CXCR6 expression and GZMB production.

scholarly journals PD-1 signaling modulates interferon-γ production by Gamma Delta (γδ) T-Cells in response to leukemia

2018 ◽  
Vol 8 (3) ◽  
pp. 1550618 ◽  
Author(s):  
Timm Hoeres ◽  
Elisabeth Holzmann ◽  
Manfred Smetak ◽  
Josef Birkmann ◽  
Martin Wilhelm
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Interferon Γ ◽  
Gamma Delta

scholarly journals Differential Activation of V γ4V δ1 and V γ9V δ2 Cord Blood Derived Gamma Delta T Cells upon Exposure to EBV-Lcl and K562 Cells

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2790-2790
Author(s):  
Jeremy Wee Kiat Ng ◽  
Joey Lai ◽  
Tony Kiat Hon Lim ◽  
William YK Hwang ◽  
Shang Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Single Cell ◽  
Γδ T Cells ◽  
Rapid Expansion ◽  
Leukemia Cell Line ◽  
Γδ T Cell ◽  
Gamma Delta

Abstract Gamma-delta (γδ) T cells have emerged as a promising candidate for adoptive cellular immunotherapy. To harness and maximize the anti-leukemia properties of these cells, we sort to comprehensively profile the transcriptomic signatures and immune repertoire of in vitro expanded γδ T cell products. Given the reported diverse TCR γδ repertoire and naïve nature of γδ T cells found in human cord blood (CB γδ), we serially track the molecular and cellular changes in these cells upon activation in expansion cultures. Based on the established viral reactivities of γδ T cell as well as prior studies showing their cross reactivities against leukemia and cancer cells, we had previously shown that stimulating CB γδ with an irradiated EBV-LCL feeder cell-based rapid expansion protocol (REP) is capable of generating cell products with potent and specific cytotoxicity against human AML cells. In the present study, using single cell RNA sequencing (scRNA-seq) coupled with single cell TCR γδ repertoire analysis, we compared the transcription signatures between our REP expanded γδ T cell (REP γδ) and non-manipulated γδ T cells reported in literatures, showing the progressive acquisition of an adult PB derived γδ T cell (PB γδ)-like cell states. Time course analysis demonstrated complex T cell activation and maturation trajectories correlating with variable level of clonal induction throughout the course of in vitro expansion. At the end of expansion, the harvested REP γδ are predominantly of the V γ4V δ1 subtype. Nevertheless, upon exposing REP γδ to target leukemia cell line K562, outgrowth of other non-V γ4V δ1 as well as the semi-invariant V γ9V δ2 cells were observed. Taken together, our data shows that as CB γδ expand and differentiate in culture, they adopt an adult PB γδ-like program. More importantly, our data highlights the rich clonal composition of in vitro expanded CB γδ, with different clonotypes being variably activated upon exposure to different stimuli. Such characteristics can potentially overcome the challenges of cancer heterogeneity and cell persistence, with the potential of improving outcomes in cell immunotherapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bovine gamma/delta T cells are stimulated by bovine coronavirus antigens identified by a soluble T cells receptor

2017 ◽  
Vol 73 (7) ◽  
pp. 412-417
Author(s):  
Felix N. Toka
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Γδ T Cells ◽  
In Vitro Study ◽  
Fold Increase ◽  
In Vitro Assays ◽  
Gamma Delta ◽  
Bovine Coronavirus ◽  
Gm Csf

Gamma/delta (γδ) T cells in cattle account for an abundant T cell population. However, little is known regarding the function of γδ T cells as immune cells compared to αβ T cells. Not many pathogen-related antigens have been defined and known to stimulate γδ T cells. To address this information gap, we constructed a soluble receptor for bovine γδ T cells (sγδTCR) that was later used to identify two proteins (156 kDa and 102 kDa) or protein fragments expressed by bovine coronavirus (BCov). The molecular weight of the larger protein suggests it could be the spike glycoprotein of BCov. Subsequently, we used the identified viral proteins to study the reactivity of bovine γδ T cells. In vitro assays showed that purified preparations of the two proteins stimulated WC1+ γδ T cells isolated from cattle. A 4-fold increase in IFN production and a significantly higher expression of MHC class II was observed. However, these viral ligands could not stimulate γδ T cells to synthesize IL-8 or GM-CSF, known to be produced by γδ T cells when stimulated with bacterial antigens. Although the γδ T cells assessed here appeared activated by way of IFN and MHC II expression, surface markers such as CD2, CD25, CD44, CD62L and CD335 were not expressed at significant levels. Further, the activation elicited by viral ligands was not sufficient to induce cytotoxic capability in γδ T cells in vitro as measured by a flow cytometry-based cytotoxicity assay. This in vitro study shows that WC1+ γδ T cells can directly recognize viral antigen

scholarly journals Association between Serum Heat Shock Proteins and Gamma-Delta T Cells—An Outdated Clue or a New Direction in Searching for an Anticancer Strategy? A Short Report

2021 ◽  
Vol 11 (16) ◽  
pp. 7325
Author(s):  
Dorota Pawlik-Gwozdecka ◽  
Justyna Sakowska ◽  
Maciej Zieliński ◽  
Magdalena Górska-Ponikowska ◽  
Francesco Cappello ◽  
...  
Keyword(s):  
T Cells ◽  
Strong Association ◽  
Γδ T Cells ◽  
Diagnostic Methods ◽  
Enzyme Linked Immunosorbent Assay ◽  
Short Report ◽  
Gamma Delta ◽  
Childhood All ◽  
Hla Dr ◽  
Shock Proteins

HSPs demonstrate a strong association with gamma-delta (γδ) T cells. Most of the studies regarding interactions between the parameters were conducted in the 1990s. Despite promising results, the concept of targeting γδ T cells by HSPs seems to be a forgotten direction due to potent non-peptidic phosphoantigens rather than HSPs have been found to be the essential stimulatory components for human γδ cells. Currently, with greater knowledge of lymphocyte diversity, and more accurate diagnostic methods, we decided to study the correlation once again in the neoplastic condition. Twenty-one children with newly diagnosed acute lymphoblastic leukaemia (ALL) were enrolled on the study. Serum HSP90 concentrations were evaluated by an enzyme-linked immunosorbent assay (ELISA), subsets of γδ T cells (CD3+ γδ, CD3+ γδ HLA/DR+, CD4+ γδ and CD8+ γδ) by flow cytometry. We have shown statistically relevant correlations between serum HSP90 and CD3+ HLA/DR+ γδ T cells in paediatric ALL at diagnosis (R = 0.53, p < 0.05), but not after induction chemotherapy. We also have demonstrated decreased levels of both serum HSP90 and CD3+ HLA/DR+ γδ T cells before treatment, which may indirectly indicate dose-dependent unknown interaction between the parameters. The results of our study may be a good introduction to research on the association between HSPs and CD3+ HLA/DR+ γδ T cells, which could be an interesting direction for the development of anti-cancer strategies, not just for childhood ALL.

Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells

Science ◽  
2020 ◽  
Vol 367 (6478) ◽  
pp. eaay5516 ◽  
Author(s):  
Marc Rigau ◽  
Simone Ostrouska ◽  
Thomas S. Fulford ◽  
Darryl N. Johnson ◽  
Katherine Woods ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Cell Receptors ◽  
Protective Immunity ◽  
Cell Activation ◽  
Molecular Targets ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Gamma Delta

Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2+ T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9+ TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell–based immunotherapies.

Combination of Low Rate of γδ T Cells and High Rate of Regulatory T Cells after Allogeneic Stem Cell Transplantation Is a Poor Prognostic Factor for Patients with Hematological Neoplasm

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5463-5463
Author(s):  
Yasuhiko Shibasaki ◽  
Syukuko Miyakoshi ◽  
Takayuki Katagiri ◽  
Kyoko Fuse ◽  
Hironori Kobayashi ◽  
...  
Keyword(s):  
T Cells ◽  
Multivariate Analysis ◽  
Relapse Rate ◽  
Acute Gvhd ◽  
Γδ T Cells ◽  
Cd4 Cells ◽  
Allogeneic Hsct ◽  
Significant Difference ◽  
Hematological Neoplasm ◽  
Cumulative Relapse Rate

Abstract After allogeneic hematopoietic stem cell transplantation (HSCT), immune recovery is important to protect the patient from relapse and co-morbidities such as graft-versus-host disease (GVHD) and infection. Various numbers of low-frequency immunocompetent cells are known to exist among T cells and each subset shows different immunological action. Among them, γδ T cells were reported to facilitate a graft-versus-leukemia (GVL) effect and regulatory T cells (Tregs) were reported to prevent acute GVHD. In this study, we focused on the clinical relevance of γδ T cells and Tregs in peripheral blood (PB) after allogeneic HSCT in patients with hematological neoplasm to outcome. We retrospectively analyzed 33 adult patients with hematological neoplasms who underwent allogeneic HSCT between July 2011 and February 2015 at Niigata University Medical and Dental Hospital, including 17 with acute myeloid leukemia, 8 with acute lymphoblastic leukemia, 4 with myelodysplastic syndromes, 2 with Epstein-Barr virus-associated lymphoproliferative disorder, 1 with adult T-cell leukemia/lymphoma and 1 with primary myelofibrosis. Circulating γδ T cells and Tregs were analyzed by flow cytometry within 30-100 days after allogeneic HSCT. γδ T cells were identified as CD3+/γδTCR+ cells. Tregs were identified as CD4+/Foxp3+/CD25+ cells. The percentage of γδ T cells was calculated by dividing by CD3+ cells. The percentage of Tregs was calculated by dividing by CD4+ cells. The Kaplan-Meier method was used to estimate the probability of disease-free survival (DFS). The Mann-Whitney U test was used to compare the percentage of γδ T cells in PB or Tregs in PB and any grade of acute GVHD or grade II-IV acute GVHD. Cumulative relapse rate and non-relapse mortality (NRM) were based on Gray's estimates. Fine-Gray proportional hazards models were used for assessment by multivariate analysis of relapse rate. Factor adjustment was performed for age, conditioning regimen, disease status and HLA compatibility. The median percentage of γδ T cells divided by CD3+ cells in PB was 3.3% (0-28.4%). The median percentage of Tregs divided by CD4+ cells in PB was 1.9% (0-17.3%). The percentage of γδ T cells in PB was not associated with the incidence of acute GVHD. In addition, the percentage of Tregs in PB was not associated with the incidence of acute GVHD. Next, we established an immune scoring system according to the percentage of γδ T cells and Tregs in PB. Less than 4% of γδ T cells as a proportion of CD3+ cells in PB was scored as 1 point and more than 4% of Tregs as a proportion of CD4+ cells in PB was scored as 1 point. The patients with 1 point for γδ T cells did not show a significant difference to the patients with 0 points in terms of cumulative relapse rate or NRM. In addition, the patients with 1 point for Tregs did not show a significant difference to the patients with 0 points in terms of cumulative relapse rate or NRM. We classified the patients into score 0-1 and score 2 upon adding the points. Patients with score 2 showed a higher relapse rate in univariate analysis (p=0.002) and multivariate analysis (hazard ratio 3.65, p=0.017) than patients with score 0-1. Moreover, patients with score 2 showed higher DFS in univariate analysis (p=0.001) and multivariate analysis (hazard ratio 3.50, p=0.027) than patients with score 0-1. Our study suggests that the combination of a low rate of γδ T cells and a high rate of Tregs in PB after allogeneic HSCT is a poor prognostic factor for patients with hematological neoplasm. In addition, it suggests that the balance of immunosuppression and immunoactivation may be important for the outcome of patients after allogeneic HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of gamma-delta (γδ) T cells in autoimmunity

2014 ◽  
Vol 97 (2) ◽  
pp. 259-271 ◽  
Author(s):  
Sourav Paul ◽  
Shilpi ◽  
Girdhari Lal
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Gamma Delta
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