scholarly journals Suppressive activity of Vδ2+ γδ T cells on αβ T cells is licensed by TCR signaling and correlates with signal strength

2020 ◽  
Vol 69 (4) ◽  
pp. 593-610 ◽  
Author(s):  
Karin Schilbach ◽  
Naomi Krickeberg ◽  
Carlotta Kaißer ◽  
Simon Mingram ◽  
Janika Kind ◽  
...  
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Signal Strength ◽  
Suppressive Activity ◽  
Tcr Signaling ◽  
Αβ T Cells

An obligate role for T-cell receptor αβ+ T cells but not T-cell receptor γδ+ T cells, B cells, or CD40/CD40L interactions in a mouse model of atopic dermatitis

2001 ◽  
Vol 107 (2) ◽  
pp. 359-366 ◽  
Author(s):  
Amy L. Woodward ◽  
Jonathan M. Spergel ◽  
Harri Alenius ◽  
Emiko Mizoguchi ◽  
Atul K. Bhan ◽  
...  
Keyword(s):  
T Cells ◽  
Atopic Dermatitis ◽  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
T Cell Receptor ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Αβ T Cells

scholarly journals γδ T cells present antigen to CD4+ αβ T cells

1998 ◽  
Vol 63 (6) ◽  
pp. 707-714 ◽  
Author(s):  
Robert A. Collins ◽  
Dirk Werling ◽  
Sara E. Duggan ◽  
A. Patricia Bland ◽  
Keith R. Parsons ◽  
...  
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Αβ T Cells

scholarly journals αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression

2021 ◽  
Vol 11 (9) ◽  
pp. 923
Author(s):  
Josephine G. M. Strijker ◽  
Ronja Pscheid ◽  
Esther Drent ◽  
Jessica J. F. van der Hoek ◽  
Bianca Koopmans ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transcriptional Profiling ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Target Cells ◽  
Γδ T Cell ◽  
Mhc I ◽  
Organization Analysis ◽  
Αβ T Cells

Currently ~50% of patients with a diagnosis of high-risk neuroblastoma will not survive due to relapsing or refractory disease. Recent innovations in immunotherapy for solid tumors are highly promising, but the low MHC-I expression of neuroblastoma represents a major challenge for T cell-mediated immunotherapy. Here, we propose a novel T cell-based immunotherapy approach for neuroblastoma, based on the use of TEG002, αβ-T cells engineered to express a defined γδ-T cell receptor, which can recognize and kill target cells independent of MHC-I. In a co-culture killing assay, we showed that 3 out of 6 neuroblastoma organoids could activate TEG002 as measured by IFNγ production. Transcriptional profiling showed this effect correlates with an increased activity of processes involved in interferon signaling and extracellular matrix organization. Analysis of the dynamics of organoid killing by TEG002 over time confirmed that organoids which induced TEG002 activation were efficiently killed independent of their MHC-I expression. Of note, efficacy of TEG002 treatment was superior to donor-matched untransduced αβ-T cells or endogenous γδ-T cells. Our data suggest that TEG002 may be a promising novel treatment option for a subset of neuroblastoma patients.

scholarly journals An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer

2019 ◽  
Vol 11 (513) ◽  
pp. eaax9364 ◽  
Author(s):  
Yin Wu ◽  
Fernanda Kyle-Cezar ◽  
Richard T. Woolf ◽  
Cristina Naceur-Lombardelli ◽  
Julie Owen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Human Breast ◽  
Cell Compartment ◽  
Αβ T Cells

Innate-like tissue-resident γδ T cell compartments capable of protecting against carcinogenesis are well established in mice. Conversely, the degree to which they exist in humans, their potential properties, and their contributions to host benefit are mostly unresolved. Here, we demonstrate that healthy human breast harbors a distinct γδ T cell compartment, primarily expressing T cell receptor (TCR) Vδ1 chains, by comparison to Vδ2 chains that predominate in peripheral blood. Breast-resident Vδ1+ cells were functionally skewed toward cytolysis and IFN-γ production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident Vδ1+ cells could be activated innately via the NKG2D receptor, whereas neighboring CD8+ αβ T cells required TCR signaling. A comparable population of Vδ1+ cells was found in human breast tumors, and when paired tumor and nonmalignant samples from 11 patients with triple-negative breast cancer were analyzed, progression-free and overall survival correlated with Vδ1+ cell representation, but not with either total γδ T cells or Vδ2+ T cells. As expected, progression-free survival also correlated with αβ TCRs. However, whereas in most cases TCRαβ repertoires focused, typical of antigen-specific responses, this was not observed for Vδ1+ cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident Vδ1+ compartments and adaptive responses mounted by αβ T cells.

Ex vivo-expanded natural killer cells kill cancer cells more effectively than ex vivo-expanded γδ T cells or αβ T cells

2014 ◽  
Vol 22 (2) ◽  
pp. 486-491 ◽  
Author(s):  
Xuewen Deng ◽  
Hiroshi Terunuma ◽  
Atsushi Terunuma ◽  
Tsubasa Takane ◽  
Mie Nieda
Keyword(s):  
T Cells ◽  
Natural Killer Cells ◽  
Cancer Cells ◽  
Natural Killer ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Killer Cells ◽  
Αβ T Cells

scholarly journals Mycobacterium-Specific γ9δ2T Cells Mediate Both Pathogen-Inhibitory and CD40 Ligand-Dependent Antigen Presentation Effects Important for Tuberculosis Immunity

2015 ◽  
Vol 84 (2) ◽  
pp. 580-589 ◽  
Author(s):  
Getahun Abate ◽  
Charles T. Spencer ◽  
Fahreta Hamzabegovic ◽  
Azra Blazevic ◽  
Mei Xia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
Cd40 Ligand ◽  
Cell Contact ◽  
Protective Effects ◽  
Inhibitory Effects ◽  
Content Type ◽  
T Cell Lines ◽  
Αβ T Cells

Numerous pathogens, includingMycobacterium tuberculosis, can activate human γ9δ2T cells to proliferate and express effector mechanisms. γ9δ2T cells can directly inhibit the growth of intracellular mycobacteria and may also act as antigen-presenting cells (APC). Despite evidence for γδ T cells having the capacity to function as APC, the mechanisms involved and importance of these effects on overall tuberculosis (TB) immunity are unknown. We preparedM. tuberculosis-specific γ9δ2T cell lines to study their direct protective effects and APC functions forM. tuberculosis-specific αβ T cells. The direct inhibitory effects on intracellular mycobacteria were measured, and the enhancing effects on proliferative and effector responses of αβ T cells assessed. Furthermore, the importance of cell-to-cell contact and soluble products for γ9δ2T cell effector responses and APC functions were investigated. We demonstrate, in addition to direct inhibitory effects on intracellular mycobacteria, the following: (i) γ9δ2T cells enhance the expansion ofM. tuberculosis-specific αβ T cells and increase the ability of αβ T cells to inhibit intracellular mycobacteria; (ii) although soluble mediators are critical for the direct inhibitory effects of γ9δ2T cells, their APC functions do not require soluble mediators; (iii) the APC functions of γ9δ2T cells involve cell-to-cell contact that is dependent on CD40-CD40 ligand (CD40L) interactions; and (iv) fully activated CD4+αβ T cells and γ9δ2T cells provide similar immune enhancing/APC functions forM. tuberculosis-specific T cells. These effector and helper effects of γ9δ2T cells further indicate that these T cells should be considered important new targets for new TB vaccines.

scholarly journals Itch−/−αβ and γδ T cells independently contribute to autoimmunity in Itchy mice

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4273-7282 ◽  
Author(s):  
Valentino Parravicini ◽  
Anne-Christine Field ◽  
Peter D. Tomlinson ◽  
M. Albert Basson ◽  
Rose Zamoyska
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Microbial Pathogens ◽  
Interleukin 4 ◽  
Cell Subpopulation ◽  
Inflammatory Condition ◽  
Independent Manner ◽  
Autoimmune Pathology ◽  
Inflammatory Phenotype ◽  
Αβ T Cells

Abstract E3 ubiquitin ligases determine which intracellular proteins are targets of the ubiquitin conjugation pathway and thus play a key role in determining the half-life, subcellular localization and/or activation status of their target proteins. Itchy mice lack the E3 ligase, Itch, and show dysregulation of T lymphocytes and the induction of a lethal autoimmune inflammatory condition. Itch is widely expressed in hematopoietic and nonhematopoietic cells, and we demonstrate that disease is transferred exclusively by hematopoietic cells. Moreover, distinct manifestations of the autoimmune inflammatory phenotype are contributed by discrete populations of lymphocytes. The presence of Itch-deficient αβ T cells drives expansion of peritoneal B1b cells and elevated IgM levels, which correlate with itching and pathology. In contrast, Itch−/− interleukin-4–producing γδ T cells, even in the absence of αβ T cells, are associated with elevated levels of IgE and an inflammatory condition. These data indicate that disruption of an E3 ubiquitin ligase in αβ T cells can subvert a B-cell subpopulation, which normally functions to control particular microbial pathogens in a T-independent manner, to contribute to autoimmunity. In addition, disruption of Itch in innate γδ T cells can influence autoimmune pathology and might therefore require distinct therapeutic intervention.

Recovery Of Gamma/Delta+ T Cells After Transplantation With Alpha-Beta+/CD19+ Lymphocyte Depleted Hematopoietic Stem Cells From HLA-Haploidentical Donors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3245-3245
Author(s):  
Irma Airoldi ◽  
Ignazia Prigione ◽  
Alice Bertaina ◽  
Claudia Cocco ◽  
Daria Pagliara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Zoledronic Acid ◽  
Γδ T Cells ◽  
Leukemia Cells ◽  
Γδ T Cell ◽  
Hematopoietic Stem ◽  
Functional Studies ◽  
Αβ T Cells ◽  
Over Time

Abstract HLA-haploidentical hematopoietic stem cell transplantation (HSCT) using CD34+ selected cells is a widely used procedure, which, however, is complicated by delayed immune reconstitution. We recently developed a new method of graft manipulation based on the physical removal of αβ+ T cells and CD19+ B cells, which permits to leave mature natural killer (NK) cells and γδ+ T cells in the graft. These cells can exert a graft-versus-leukemia (GvL) effect and reduce the risk of infection. In particular, unconventional γδ T cells play a critical role in both innate and adaptive immunity and exert HLA-unrestricted cytotoxicity against both solid and hematological tumors, thus potentially acting as beneficial effector cells in transplanted patients. Moreover, such grafts may limit the risk of graft-versus-host disease and prevent EBV-related lymphoproliferative disease. We performed phenotypic and functional studies on γδ T cells collected from 20 pediatric patients (pts, 13 males, 7 females, median age 10 years, range 6 months to 16 years) that received this type of allograft. Eighteen pts had acute leukemia and 2 non-malignant disorders. Ex vivo assays of peripheral blood γδ T cell phenotype and function were performed weekly until Hospital discharge and monthly until 6 months after HSCT. Phenotype of γδ T cells was analysed by flow cytometry. Analyses were performed on mononuclear cells labelled with mAb panels (CD3, CD45, pan-γδ, anti-Vδ1, -Vδ2, -Vγ9, CD45RO, CD45RA, CD27, CD16, CD56) allowing the identification of the main γδ+ T cell subsets, including Vδ1+ and Vδ2+ cells, naïve, central memory (CM), effector memory (EM) and terminally differentiated (TD) γδ T cells. Functional studies were performed using γδ T cells shortly after collection from pts, as well as after in vitro expansion with zoledronic acid and IL-2 for 10 days. Cytotoxic activity of γδ T cells was tested against primary leukemia cells, through CD107a degranulation assay and/or standard 51Cr-release assay. In the first 4 weeks after HSCT, T cells were consistently of the γδ subset (>90% of CD45+CD3+ cells); by contrast, αβ+ T cells gradually increased over time. In approximately half of the pts, the percentage of αβ T cells exceeded that of γδ T cells already starting from 30 days after HSCT. γδ T cells consisted of Vδ2+Vγ9+ and Vδ1+Vγ9+/- cells, and marginally of the Vδ1-Vδ2-Vγ9- population. Detailed phenotypic characterization of Vδ1+ and Vδ2+ γδ T cells revealed that, at day +20 after HSCT, 44% of Vδ1+ cells were CM (identified as CD45RO+CD27+ cells), 26% naïve (CD45RO-CD27+), 21.4% TD (CD45RO-CD27-) and 6.1% EM (CD45RO+CD27-). Similarly, 55.4% of Vδ2+ γδ T lymphocytes were CM, 9.8% naïve, 11.4% TD and 23.1% EM. The proportion of the different Vδ2+ γδ T cell subset did not change significantly over time, especially when comparing that present at day +20 after HSCT (time point, TP1) with that measured 30 days after the attainment of a 1:1 ratio of αβ-to- γδ T cells (TP2) (Figure 1, left panel). By contrast, by comparing TP1 and TP2, we found that Vδ1+ CM γδ T cells decreased and EM cells increased over time, while naïve or TD Vδ1+ γδ T cells did not change (Figure 1, right panel). In transplanted pts experiencing cytomegalovirus (CMV) reactivation, γδ T cells mostly consisted of Vδ1+ cells (mean 59.8% of γδ T cells), among which 49% were TD, 22.7% EM, 18.9% CM and 10.1% naïve. Noteworthy, in transplanted pts who did not have CMV reactivation, the main γδ T cells showed a Vδ2+ phenotype. Functional studies revealed that pt-derived γδ T cells consistently expanded in vitro after exposure to zoledronic acid and IL-2, the resulting Vγ9Vδ2 population expressing mainly an EM phenotype. These Vγ9Vδ2 cells exerted cytotoxic activities against primary allogeneic leukemia cells, especially when leukemia cells were pre-treated with zoledronic acid (Figure 2). More importantly, both Vδ1+ and Vδ2+ γδ T cells obtained from transplanted pts showed cytotoxic activity against primary leukemia cells, as assessed by CD107a degranulation assay. In conclusion, we provide the first phenotypic and functional characterization of γδ T cells, analyzed over time in children transplanted with grafts depleted of αβ+ T cells and of B lymphocytes. Our results support the concept that γδ T cells are important effector cells, which can be expanded and activated after exposure to bisphosphonates and IL-2 with the aim of improving their killing capacity against leukemia cells. Disclosures: No relevant conflicts of interest to declare.

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