scholarly journals Diversity of Tumor-Infiltrating, γδ T-Cell Abundance in Solid Cancers

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1537 ◽  
Author(s):  
Ghita Chabab ◽  
Florence Boissière-Michot ◽  
Caroline Mollevi ◽  
Jeanne Ramos ◽  
Evelyne Lopez-Crapez ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Γδ T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Pancreatic Tumors ◽  
Cell Detection ◽  
Cancer Type ◽  
Γδ T Cell ◽  
Cancer Types ◽  
T Cell Subpopulations

γδ T-cells contribute to the immune response against many tumor types through their direct cytolytic functions and their capacity to recruit and regulate the biological functions of other immune cells. As potent effectors of the anti-tumor immune response, they are considered an attractive therapeutic target for immunotherapies, but their presence and abundance in the tumor microenvironment are not routinely assessed in patients with cancer. Here, we validated an antibody for immunohistochemistry analysis that specifically detects all γδ T-cell subpopulations in healthy tissues and in the microenvironment of different cancer types. Tissue microarray analysis of breast, colon, ovarian, and pancreatic tumors showed that γδ T-cell density varies among cancer types. Moreover, the abundance of γδ tumor-infiltrating lymphocytes was variably associated with the outcome depending on the cancer type, suggesting that γδ T-cell recruitment is influenced by the context. These findings also suggest that γδ T-cell detection and analysis might represent a new and interesting diagnostic or prognostic marker.

scholarly journals Identification of leptospiral protein antigens recognized by WC1+ γδ T cell subsets as target for development of recombinant vaccines

2021 ◽  
Author(s):  
Aline Teixeira ◽  
Alexandria Gillespie ◽  
Alehegne Yirsaw ◽  
Emily Britton ◽  
Janice Telfer ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Outer Membrane Proteins ◽  
Γδ T Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Economic Losses ◽  
Γδ T Cell ◽  
Protein Antigens

Pathogenic Leptospira species cause leptospirosis, a neglected zoonotic disease recognized as a global public health problem. It is also the cause of the most common cattle infection that results in major economic losses due to reproductive problems. γδ T cells play a role in the protective immune response in livestock species against Leptospira while human γδ T cells also respond to Leptospira. Thus, activation of γδ T cells has emerged as a potential component for optimization of vaccine strategies. Bovine γδ T cells proliferate and produce IFN-γ in response to vaccination with inactivated leptospires and this response is mediated by a specific subpopulation of the WC1-bearing γδ T cells. WC1 molecules are members of the group B scavenger receptor cysteine rich (SRCR) superfamily and are composed of multiple SRCR domains, of which particular extracellular domains act as ligands for Leptospira. Since WC1 molecules function as both pattern recognition receptors and γδ TCR coreceptors, the WC1 system has been proposed as a novel target to engage γδ T cells. Here, we demonstrate the involvement of leptospiral protein antigens in the activation of WC1+ γδ T cells and identified two leptospiral outer membrane proteins able to interact directly with them. Interestingly, we show that the protein-specific γδ T cell response is composed of WC1.1+ and WC1.2+ subsets, although a greater number of WC1.1+ γδ T cells respond. Identification of protein antigens will enhance our understanding of the role γδ T cells play in the leptospiral immune response and in recombinant vaccine development.

Characterization of a Unique γδ T-Cell Subset as a Specific Marker of Cytomegalovirus Infection Severity

2020 ◽  
Author(s):  
Hannah Kaminski ◽  
Coline Ménard ◽  
Bouchra El Hayani ◽  
And-Nan Adjibabi ◽  
Gabriel Marsères ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
Γδ T Cells ◽  
Specific Marker ◽  
Dependent Manner ◽  
Γδ T Cell ◽  
T Cell Subset ◽  
Cmv Disease

Abstract Cytomegalovirus (CMV) is a major infectious cause of death and disease after transplantation. We have previously demonstrated that the tissue-associated adaptive Vδ2neg γδ T cells are key effectors responding to CMV and associated with recovery, contrasting with their innatelike circulating counterparts, the Vγ9posVδ2pos T cells that respond to phosphoantigens but not to CMV. A third Vγ9negVδ2pos subgroup with adaptive functions has been described in adults. In the current study, we demonstrate that these Vγ9negVδ2pos T cells are also components of the CMV immune response while presenting with distinct characteristics from Vδ2neg γδ T cells. In a cohort of kidney transplant recipients, CMV seropositivity was the unique clinical parameter associated with Vγ9negVδ2pos T-cell expansion and differentiation. Extensive phenotyping demonstrated their substantial cytotoxic potential and activation during acute CMV primary infection or reinfection. In vitro, Vγ9negVδ2pos T cells responded specifically to CMV-infected cells in a T-cell receptor–dependent manner and through strong interferon γ production. Finally, Vγ9negVδ2pos T cells were the only γδ T-cell subset in which expansion was tightly correlated with the severity of CMV disease. To conclude, our results identify a new player in the immune response against CMV and open interesting clinical perspectives for using Vγ9negVδ2pos T cells as an immune marker for CMV disease severity in immunocompromised patients.

Immune Response of Human Propagated γδ-T-Cells to Neuroblastoma Recommend the Vδ1+ Subset for γδ-T-cell–based Immunotherapy

2008 ◽  
Vol 31 (9) ◽  
pp. 896-905 ◽  
Author(s):  
Karin Schilbach ◽  
Klaus Frommer ◽  
Sybille Meier ◽  
Rupert Handgretinger ◽  
Matthias Eyrich
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
Γδ T Cell

scholarly journals Human papillomavirus oncoproteins induce a reorganization of epithelial-associated γδ T cells promoting tumor formation

2017 ◽  
Vol 114 (43) ◽  
pp. E9056-E9065 ◽  
Author(s):  
Dorien Van hede ◽  
Barbara Polese ◽  
Chantal Humblet ◽  
Anneke Wilharm ◽  
Virginie Renoux ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
Γδ T Cells ◽  
Tumor Formation ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
Cell Subpopulations ◽  
T Cell Subpopulations ◽  
The Impact

It has been shown that γδ T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of γδ T cells in human papillomavirus (HPV)-associated uterine cervical SCC, the third-leading cause of death by cancer in women, is unknown. Here, we investigated the impact of γδ T cells in a transgenic mouse model of carcinogenesis induced by HPV16 oncoproteins. Surprisingly, γδ T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16 oncoproteins induced a decrease in epidermal Skint1 expression and the associated antitumor Vγ5+ γδ T cells, which were replaced by γδ T-cell subsets (mainly Vγ6+ γδlowCCR2+CCR6−) actively producing IL-17A. Consistent with a proangiogenic role, γδ T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A+ γδ T cells could only be observed at the cancer stage (SCC), where HPV oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16 oncoproteins induce a reorganization of the local epithelial-associated γδ T-cell subpopulations, thereby promoting angiogenesis and cancer development.

scholarly journals HIV-1-Induced Impairment of Dendritic Cell Cross Talk with γδ T Lymphocytes

2015 ◽  
Vol 89 (9) ◽  
pp. 4798-4808 ◽  
Author(s):  
Marco Cardone ◽  
Kyojiro N. Ikeda ◽  
Barbara Varano ◽  
Sandra Gessani ◽  
Lucia Conti
Keyword(s):  
Immune Response ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cross Talk ◽  
Cell Activation ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Hiv 1

ABSTRACTThe interplay between dendritic cells (DC) and γδ T lymphocytes represents a network of paracrine and cell contact interactions important for an integrated immune response to pathogens. HIV-1 infection dramatically affects the number and functions of both cell populations, and DC/γδ T cell cross talk may represent a target of virus-induced immune escape. We investigated whether HIV-exposed DC could deliver aberrant signals to interacting γδ T cells. Here we report that the interaction of human γδ T lymphocytes with HIV-1-exposed autologous monocyte-derived DC, but not direct exposure to the virus, impairs lymphocyte expansion and gamma interferon (IFN-γ) production in response to phosphoantigens. This effect is independent of virus strain and occurred in 55% of the donors analyzed. The donor-dependent variation observed relies on the responsiveness of DC to HIV-1 and is strictly related to the capacity of the virus to suppress the maturation-induced expression of interleukin 12 (IL-12). In fact, γδ T cell response to phosphoantigens is almost completely recovered when this cytokine is exogenously added to the DC/lymphocyte cocultures. Interestingly, we show that γδ T lymphocytes are recruited by HIV-1-exposed DC through a CCR5-mediated mechanism and exert a CCL4-mediated control on virus dissemination within DC and susceptible CD4+T lymphocytes. These results demonstrate an association between HIV-induced DC dysfunction and alterations of γδ T cell responses. The aberrant cross talk between these two cell populations may contribute to the pathogenesis of HIV infection by further reducing the strength of antiviral immune response.IMPORTANCEThis study provides new evidence on the mechanisms exploited by HIV-1 to evade the host immune response. We report that HIV-1 impairs the cross talk between DC and γδ T lymphocytes, by reducing the capacity of DC to promote functional γδ T cell activation. Interestingly, the virus does notper seinterfere with γδ T cell activation, thus highlighting the key role of early DC–HIV-1 interaction in this phenomenon. Furthermore, the results obtained unravel the novel role of γδ T cells in controlling HIV-1 dissemination within the DC population as well as virus transfer to susceptible CD4+T lymphocytes. The interactions of DC with innate lymphocytes represent a major control mechanism for an integrated immune response to infection. Understanding how HIV-1 harnesses these pathways may provide important insights on the pathogenesis of disease and offer new opportunities for therapeutic interventions.

Inhibition of γδ T Cell Proliferation by CD4+CD25+FOXP3+ Regulatory T Cells (Treg).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1742-1742
Author(s):  
Volker Kunzmann ◽  
Brigitte Kimmel ◽  
Judith Engert ◽  
Martin Wilhelm ◽  
Hermann Einsele
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Γδ T Cells ◽  
T Cell Proliferation ◽  
Γδ T Cell ◽  
Cell Ratio ◽  
Vγ9vδ2 T Cells

Abstract CD4+CD25+FOXP3+ regulatory T cells (Treg) are a unique population of T cells that maintain immune tolerance by suppressing self-reactive cells. Treg also contribute to the establishment of a dominant tolerance during infections and after allogeneic transplantation and suppress immune response to tumors. Increasing evidence supports the existence of elevated numbers of Treg in both solid tumors and hematological malignancies. In this study we show that Treg may also suppress other arms of an effective immune response. In vitro, purified human CD4+CD25+FOXP3+ Treg (by immunomagnetic selection) directly inhibit phosphoantigen (BrHPP)-mediated proliferation of Vγ9Vδ2 T cells, the major γδ T lymphocyte subset in humans. Importantly, suppression of γδ T cell proliferation by Treg was maintained when Treg where separated from γδ T cells by Transwells, suggesting that the inhibitory function of Treg on γδ T cell proliferation is not cell-contact independent and rather soluble factors produced by Treg contribute to this suppressive effect. However, Treg do neither influence the expression of activation markers (CD69, CD25) nor the production of IFN-γ by Vγ9Vδ2 T cells stimulated with phosphoantigen indicating that not all effector functions of Vγ9Vδ2 T cells are suppressed by Treg. As we have recently reported, phosphoantigen-mediated γδ T cell proliferation is frequently suppressed in cancer patients. This observation prompted us to address the role of Treg in controlling γδ T cell proliferation in cancer patients. An inverse correlation between Treg frequencies (i.e. the ratio between Treg and Vγ9Vδ2 T cells) in peripheral blood and phosphoantigen-mediated γδ T cell proliferation was found (mean Treg/Vγ9Vδ2 T cell ratio in cancer patients with maintained phosphoantigen-mediated γδ T cell proliferation (n=14): 4.06; mean Treg/Vγ9Vδ2 T cell ratio in cancer patients without phosphoantigen-mediated γδ T cell proliferation (n=55): 33.36)). Therefore, the Treg/Vγ9Vδ2 T cell ratio in peripheral blood can predict the capacity of γδ T cells to proliferate in response to phosphoantigens. In conclusion, these findings support a role for Treg in blunting the γδ T cell arm of the innate immune response in cancer patients and highlight the potential of Treg depletion (e.g. by anti-CD25 antibodies, cyclophosphamide or fludarabine) to promote γδ T cell mediated antitumor activity.

scholarly journals Mining hub genes correlated with immune infiltrating level across multiple tumors microenvironment

2020 ◽  
Author(s):  
Ning Zhao ◽  
Liang Wu ◽  
Zili Zhou ◽  
Xudan Zhang ◽  
Shengbo Han ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Tyrosine Phosphatase ◽  
Enrichment Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Functional Enrichment ◽  
Cancer Type ◽  
Hub Genes ◽  
Multiple Tumors ◽  
Cancer Types

Abstract Background Previous studies revealed that cancer-associated differentially expressed genes (DEGs) in an independent cancer type are rarely related to the tumorigenesis and metastasis, while the common DEGs across multiple types of cancer may be proved as potential oncogenes or tumor suppressors and extend our understanding. Although tumor-infiltrating lymphocytes (TIL) have been reported to be associated with prognosis in multiple types of cancer, the hub genes regulating immune cells function in different cancer types remain unclear.Methods To screen for the hub genes regulating immune infiltrating level across multiple tumors microenvironment, the raw data containing RNA sequencing and clinical information from TCGA database and immune scores from ESTIMATE website across 25 cancer types were obtained.Results Based on the immune scores, all cases were categorized into high-score and low-score groups. Kaplan–Meier survival analysis demonstrated that a strong correlation was found in six cancer types. The functional enrichment analysis of common DEGs revealed that infection and immune response are the most prominent biological characteristics. Subsequently, the twelve common DEGs with prognostic value were identified as candidate hub genes and were adopted to construct the PPI network. Because of highly interconnected with other hub genes, protein tyrosine phosphatase non-receptor type 6 (PTPN6) was selected as the real hub gene across the six immune-specific tumors.Conclusion Due to the significant correlation between PTPN6 with tumor-infiltrating immune cells in multiple cancers, PTPN6 may well play a vital role in regulating immune response for tumor development.

scholarly journals Long-term expansion of effector/memory Vδ2− γδ T cells is a specific blood signature of CMV infection

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1317-1324 ◽  
Author(s):  
Vincent Pitard ◽  
David Roumanes ◽  
Xavier Lafarge ◽  
Lionel Couzi ◽  
Isabelle Garrigue ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Adaptive Immune Response ◽  
Γδ T Cells ◽  
Effector Memory ◽  
Γδ T Cell ◽  
Cmv Infection ◽  
Adaptive Immune

Abstract The ability of human γδ T cells to develop immunologic memory is still a matter of debate. We previously demonstrated the involvement of Vδ2− γδ T lymphocytes in the response of immunosuppressed organ recipients to cytomegalovirus (CMV). Here, we demonstrate their ability to mount an adaptive immune response to CMV in immunocompetent subjects. Vδ2− γδ T-cell peripheral blood numbers, repertoire restriction, and cytotoxicity against CMV-infected fibroblasts were markedly increased in CMV-seropositive, compared with CMV-seronegative, healthy persons. Whereas Vδ2− γδ T cells were found as naive cells in CMV− patients, they virtually all exhibited the cytotoxic effector/memory phenotype in CMV+ patients, which is also observed in transplanted patients challenged with CMV. This long-term complete remodeling of the Vδ2− γδ T-cell population by CMV predicts their ability to exhibit an adaptive anti-CMV immune response. Consistent with this, we observed that the secondary response to CMV was associated with a faster γδ T-cell expansion and a better resolution of infection than the primary response. In conclusion, the increased level of effector-memory Vδ2− γδ T cells in the peripheral blood is a specific signature of an adaptive immune response to CMV infection of both immunocompetent and immunosuppressed patients.

scholarly journals The role of unconventional T cells in COVID-19

2021 ◽  
Author(s):  
Kristen Orumaa ◽  
Margaret R. Dunne
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Treatment Strategies ◽  
Γδ T Cells ◽  
Protective Role ◽  
T Cell Subsets ◽  
Viral Immunity ◽  
Mait Cells

AbstractCOVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a worldwide pandemic was declared due to the easily transmissible nature of the virus. Research to date on the immune response to SARS-CoV-2 has focused largely on conventional B and T lymphocytes. This review examines the emerging role of unconventional T cell subsets, including γδ T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells in human SARS-CoV-2 infection.Some of these T cell subsets have been shown to play protective roles in anti-viral immunity by suppressing viral replication and opsonising virions of SARS-CoV. Here, we explore whether unconventional T cells play a protective role in SARS-CoV-2 infection as well. Unconventional T cells are already under investigation as cell-based immunotherapies for cancer. We discuss the potential use of these cells as therapeutic agents in the COVID-19 setting. Due to the rapidly evolving situation presented by COVID-19, there is an urgent need to understand the pathogenesis of this disease and the mechanisms underlying its immune response. Through this, we may be able to better help those with severe cases and lower the mortality rate by devising more effective vaccines and novel treatment strategies.

scholarly journals CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

2021 ◽  
Vol 9 (4) ◽  
pp. e002051
Author(s):  
Ryan Michael Reyes ◽  
Yilun Deng ◽  
Deyi Zhang ◽  
Niannian Ji ◽  
Neelam Mukherjee ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Combination Treatment ◽  
Treatment Efficacy ◽  
Interleukin 2 ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Γδ T Cell

BackgroundAnti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in <30% of patients. Interleukin (IL)-2/αIL-2 complexes (IL-2c) that preferentially target IL-2 receptor β (CD122) augment CD8+ antitumor T cells known to improve αPD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.MethodsWe studied mechanisms of IL-2c and αPD-L1 efficacy using PD-L1+ mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites.ResultsIL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to αPD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8+ T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas γδ T cells, not reported to contribute to αPD-L1 efficacy, were indispensable for IL-2c efficacy there. αPD-L1 responsiveness in bladder required conventional T cells as expected, but not γδ T cells, altogether defining distinct mechanisms for IL-2c and αPD-L1 efficacy. γδ T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and/or tumor-specific γδ T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral γδ T cell content, activation status, and specific γδ T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor αPD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8+ T cells but not γδ T cells.ConclusionsMechanistic insights into differential IL-2c and αPD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into γδ T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus αPD-L1 to treat refractory lung metastases.

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