scholarly journals Human cytomegalovirus elicits fetal γδ T cell responses in utero

2010 ◽  
Vol 207 (4) ◽  
pp. 807-821 ◽  
Author(s):  
David Vermijlen ◽  
Margreet Brouwer ◽  
Catherine Donner ◽  
Corinne Liesnard ◽  
Marie Tackoen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Human Cytomegalovirus ◽  
Early Life ◽  
Γδ T Cells ◽  
In Utero ◽  
Γδ T Cell ◽  
Cmv Infection ◽  
Cell Responses ◽  
Ifn Γ

The fetus and infant are highly susceptible to viral infections. Several viruses, including human cytomegalovirus (CMV), cause more severe disease in early life compared with later life. It is generally accepted that this is a result of the immaturity of the immune system. γδ T cells are unconventional T cells that can react rapidly upon activation and show major histocompatibility complex–unrestricted activity. We show that upon CMV infection in utero, fetal γδ T cells expand and become differentiated. The expansion was restricted to Vγ9-negative γδ T cells, irrespective of their Vδ chain expression. Differentiated γδ T cells expressed high levels of IFN-γ, transcription factors T-bet and eomes, natural killer receptors, and cytotoxic mediators. CMV infection induced a striking enrichment of a public Vγ8Vδ1-TCR, containing the germline-encoded complementary-determining-region-3 (CDR3) δ1–CALGELGDDKLIF/CDR3γ8–CATWDTTGWFKIF. Public Vγ8Vδ1-TCR–expressing cell clones produced IFN-γ upon coincubation with CMV-infected target cells in a TCR/CD3-dependent manner and showed antiviral activity. Differentiated γδ T cells and public Vγ8Vδ1-TCR were detected as early as after 21 wk of gestation. Our results indicate that functional fetal γδ T cell responses can be generated during development in utero and suggest that this T cell subset could participate in antiviral defense in early life.

scholarly journals Characterization of Adaptive-like γδ T Cells in Ugandan Infants during Primary Cytomegalovirus Infection

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1987
Author(s):  
Jessica Tuengel ◽  
Sanya Ranchal ◽  
Alexandra Maslova ◽  
Gurpreet Aulakh ◽  
Maria Papadopoulou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
Cmv Infection ◽  
Cell Responses ◽  
Age Dependent

Gamma-delta (γδ) T cells are unconventional T cells that help control cytomegalovirus (CMV) infection in adults. γδ T cells develop early in gestation, and a fetal public γδ T cell receptor (TCR) clonotype is detected in congenital CMV infections. However, age-dependent γδ T cell responses to primary CMV infection are not well-understood. Flow cytometry and TCR sequencing was used to comprehensively characterize γδ T cell responses to CMV infection in a cohort of 32 infants followed prospectively from birth. Peripheral blood γδ T cell frequencies increased during infancy, and were higher among CMV-infected infants relative to uninfected. Clustering analyses revealed associations between CMV infection and activation marker expression on adaptive-like Vδ1 and Vδ3, but not innate-like Vγ9Vδ2 γδ T cell subsets. Frequencies of NKG2C+CD57+ γδ T cells were temporally associated with the quantity of CMV shed in saliva by infants with primary infection. The public γδ TCR clonotype was only detected in CMV-infected infants <120 days old and at lower frequencies than previously described in fetal infections. Our findings support the notion that CMV infection drives age-dependent expansions of specific γδ T cell populations, and provide insight for novel strategies to prevent CMV transmission and disease.

scholarly journals γδ T Cells in Immunity Induced by Mycobacterium bovis Bacillus Calmette-Guérin Vaccination

2004 ◽  
Vol 72 (3) ◽  
pp. 1504-1511 ◽  
Author(s):  
Jinhee Lee ◽  
Keumhwa Choi ◽  
Michael R. Olin ◽  
Sang-Nae Cho ◽  
Thomas W. Molitor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Γδ T Cell ◽  
Bcg Vaccination ◽  
Cell Responses ◽  
Ifn Γ ◽  
Time Point

ABSTRACT Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination is efficacious for newborns or adults with no previous exposure to environmental mycobacteria. To determine the relative contribution and the nature of γδ T-cell receptor-positive T cells in newborns, compared to CD4+ T cells, in immunity induced by M. bovis BCG vaccination, 4-week-old specific-pathogen-free pigs were vaccinated with M. bovis BCG and monitored by following the γδ T-cell immune responses. A flow cytometry-based proliferation assay and intracellular staining for gamma interferon (IFN-γ) were used to examine γδ T-cell responses. Pigs were found to mount Th1-like responses to M. bovis BCG vaccination as determined by immunoproliferation and IFN-γ production. The γδ T-cell lymphoproliferation and IFN-γ production to stimulation with mycobacterial antigens were significantly enhanced by M. bovis BCG vaccination. The relative number of proliferating γδ T cells after stimulating peripheral blood mononuclear cells with Mycobacterium tuberculosis H37Rv culture filtrate protein was higher than that of CD4+ T cells at an early time point after M. bovis BCG vaccination, but CD4+ T cells were found to be more abundant at a later time point. Although the γδ T-cell responses were dependent on the presence of CD4+ T cells for the cytokine interleukin-2, the enhanced γδ T cells were due to the intrinsic changes of γδ T cells caused by M. bovis BCG vaccination rather than being due solely to help from CD4+ T cells. Our study shows that γδ T cells from pigs at early ages are functionally enhanced by M. bovis BCG vaccination and suggests an important role for this T-cell subset in acquired immunity conferred by M. bovis BCG vaccination.

CD56+ human blood dendritic cells effectively promote TH1-type γδ T-cell responses

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4422-4431 ◽  
Author(s):  
Georg Gruenbacher ◽  
Hubert Gander ◽  
Andrea Rahm ◽  
Walter Nussbaumer ◽  
Nikolaus Romani ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Blood ◽  
Γδ T Cells ◽  
Rapid Expansion ◽  
Γδ T Cell ◽  
Hla Dr ◽  
Tnf Α ◽  
Ifn Γ

Abstract CD56+ human dendritic cells (DCs) have recently been shown to differentiate from monocytes in response to GM-CSF and type 1 interferon in vitro. We show here that CD56+ cells freshly isolated from human peripheral blood contain a substantial subset of CD14+CD86+HLA-DR+ cells, which have the appearance of intermediate-sized lymphocytes but spontaneously differentiate into enlarged DC-like cells with substantially increased HLA-DR and CD86 expression or into fully mature CD83+ DCs in response to appropriate cytokines. Stimulation of CD56+ cells containing both DCs and abundant γδ T cells with zoledronate and interleukin-2 (IL-2) resulted in the rapid expansion of γδ T cells as well as in IFN-γ, TNF-α, and IL-1β but not in IL-4, IL-10, or IL-17 production. IFN-γ, TNF-α, and IL-1β production were almost completely abolished by depleting CD14+ cells from the CD56+ subset before stimulation. Likewise, depletion of CD14+ cells dramatically impaired γδ T-cell expansion. IFN-γ production could also be blocked by neutralizing the effects of endogenous IL-1β and TNF-α. Conversely, addition of recombinant IL-1β, TNF-α, or both further enhanced IFN-γ production and strongly up-regulated IL-6 production. Our data indicate that CD56+ DCs from human blood are capable of stimulating CD56+ γδ T cells, which may be harnessed for immunotherapy.

scholarly journals Characterization of local and circulating bovine γδ T cell responses to respiratory BCG vaccination

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mariana Guerra-Maupome ◽  
Jodi L. McGill
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
Memory Cell ◽  
Effector Memory ◽  
Γδ T Cell ◽  
Respiratory Mucosa ◽  
Bcg Vaccination ◽  
Cell Responses

Abstract The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine is administered parenterally to infants and young children to prevent tuberculosis (TB) infection. However, the protection induced by BCG is highly variable and the vaccine does not prevent pulmonary TB, the most common form of the illness. Until improved TB vaccines are available, it is crucial to use BCG in a manner which ensures optimal vaccine performance. Immunization directly to the respiratory mucosa has been shown to promote greater protection from TB in animal models. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. Their positioning in the respiratory mucosa ensures their engagement in the response to aerosolized TB vaccination. However, our understanding of the effect of respiratory BCG vaccination on γδ T cell responses in the lung is unknown. In this study, we used a calf model to investigate the immunogenicity of aerosol BCG vaccination, and the phenotypic profile of peripheral and mucosal γδ T cells responding to vaccination. We observed robust local and systemic M. bovis-specific IFN-γ and IL-17 production by both γδ and CD4 T cells. Importantly, BCG vaccination induced effector and memory cell differentiation of γδ T cells in both the lower airways and peripheral blood, with accumulation of a large proportion of effector memory γδ T cells in both compartments. Our results demonstrate the potential of the neonatal calf model to evaluate TB vaccine candidates that are to be administered via the respiratory tract, and suggest that aerosol immunization is a promising strategy for engaging γδ T cells in vaccine-induced immunity against TB.

Quantitative and Functional Alterations of the Gamma Delta T-Cell Subset within Follicular Lymphoma Microenvironment.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2601-2601
Author(s):  
Sophie de Guibert ◽  
Jean-Baptiste Thibert ◽  
Céline Bonnaventure ◽  
Patricia Ame-Thomas ◽  
Céline Pangault ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Peripheral Blood ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Ifn Γ ◽  
Nonpeptide Antigens

Abstract T cells carrying a γδ TCR account for less than 5% of CD3pos T cells in healthy individuals but are key effectors of innate immunity through the recognition of some unprocessed nonpeptide antigens of both self and foreign origin. Whereas the Vδ2 subpopulation represents more than 70% of peripheral blood γδ T cells, the Vδ1 subset is mainly located in the mucosal tissue. Increasing evidence suggest that γδ T cells have potent antitumor activity and are implicated in the defense against some haematological and epithelial malignancies. Moreover, Vδ2 T cells constitute an attractive immunotherapy strategy since they could be expanded and activated both in vivo and in vitro using synthetic phosphoantigens and aminobiphosphonates. Such strategies are currently tested in preliminary clinical trials, notably in follicular lymphoma (FL). However, an exhaustive phenotypic and functional characterisation of γδ T cells in this disease, including tumor infiltration, is still lacking. We first explored the composition of FL microenvironment using a multicolour flow cytometry analysis. We observed a significant decrease in the percentage of myeloid (LinnegCD11cposHLADRpos) and plasmacytoid (LinnegCD123posHLADRpos) dendritic cells (P = .0011 and P &lt; .0001, respectively) in FL compared to normal secondary lymphoid organs. In addition, among CD3pos T cells, the proportion of follicular helper T cells (CD4posCXCR5posICOShi) was increased (P = .001) whereas regulatory T-cell (CD4posCD25posfoxp3pos) frequency was not altered. When considering the γδ T-cell compartment, we first highlighted a reduction of the Vδ2 subset in normal tonsils (Vδ2 = 23.48 ± 0.15% of γδ T cells, n = 11) when compared with peripheral blood. Remaining non-δ2 γδT cells were predominantly δ1 T cells. More importantly, infiltrating γδ T cells were significantly decreased in lymph node biopsies from FL patients (mean = 0.48 ± 0.4% of CD3pos T cells; n = 27) when compared both to normal tonsils (mean = 2.49 ± 1.6% of CD3pos T cells; n = 33) (P &lt; .0001) and reactive lymph nodes (mean = 2.64 ± 2.6% of CD3pos T cells; n = 9) (P = .0009). This reduction affected both the Vδ1 and Vδ2 T-cell subsets. The functionality of γδ T cells was then assessed by the measurement of cell expansion and production of IFN-γ upon stimulation with the isopentenyl pyrophosphate (IPP) phosphoantigen. Amplification rate in vitro reached 14.6 ± 4.6 fold in tonsils (n = 10) but only 4.36 ± 1.9 fold in FL samples (n = 7) (P &lt; .002) after 5 days of culture in the presence of IPP + IL-2 + IL-15. When focusing on the δ2 subset, this difference was further increased with a 40-fold amplification in tonsil and a 3-fold amplification in FL samples (P = .0004). Evaluation of IFN-γ production using ELISPOT assay revealed a high heterogeneity among tumor samples since 1 to 40% of δ2 T cells were able to respond to IPP stimulation (n = 7). Preliminary data argued for an association between the quantity and the functionality of γδ T cells in FL tumors. In conclusion, we reported an alteration of γδ T cell frequency and functionality within FL tumor niche. The next purpose will be to correlate these in vitro defects with in vivo clinical responses to immunotherapy strategies targeting γδ T cells.

scholarly journals Genetic models reveal origin, persistence and non-redundant functions of IL-17–producing γδ T cells

2018 ◽  
Vol 215 (12) ◽  
pp. 3006-3018 ◽  
Author(s):  
Inga Sandrock ◽  
Annika Reinhardt ◽  
Sarina Ravens ◽  
Christoph Binz ◽  
Anneke Wilharm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Diphtheria Toxin ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Fetal Thymus ◽  
Effector Cells ◽  
Cell Functions ◽  
Ifn Γ ◽  
Redundant Functions

γδ T cells are highly conserved in jawed vertebrates, suggesting an essential role in the immune system. However, γδ T cell–deficient Tcrd−/− mice display surprisingly mild phenotypes. We hypothesized that the lack of γδ T cells in constitutive Tcrd−/− mice is functionally compensated by other lymphocytes taking over genuine γδ T cell functions. To test this, we generated a knock-in model for diphtheria toxin–mediated conditional γδ T cell depletion. In contrast to IFN-γ–producing γδ T cells, IL-17–producing γδ T cells (Tγδ17 cells) recovered inefficiently after depletion, and their niches were filled by expanding Th17 cells and ILC3s. Complementary genetic fate mapping further demonstrated that Tγδ17 cells are long-lived and persisting lymphocytes. Investigating the function of γδ T cells, conditional depletion but not constitutive deficiency protected from imiquimod-induced psoriasis. Together, we clarify that fetal thymus-derived Tγδ17 cells are nonredundant local effector cells in IL-17–driven skin pathology.

Biology of porcine T lymphocytes

2006 ◽  
Vol 7 (1-2) ◽  
pp. 81-96 ◽  
Author(s):  
Wasin Charerntantanakul ◽  
James A. Roth
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Subset ◽  
Γδ T Cells ◽  
T Cell Responses ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
T Cell Subset ◽  
Cell Responses

The present review concentrates on the biological aspects of porcine T lymphocytes. Their ontogeny, subpopulations, localization and trafficking, and responses to pathogens are reviewed. The development of porcine T cells begins in the liver during the first trimester of fetal life and continues in the thymus from the second trimester until after birth. Porcine T cells are divided into two lineages, based on their possession of the [@@@]\rmalpha [@@@]β or γδ T-cell receptor. Porcine [@@@]\rmalpha [@@@]β T cells recognize antigens in a major histocompatibility complex (MHC)-restricted manner, whereas the γδ T cells recognize antigens in a MHC non-restricted fashion. The CD4+CD8−and CD4+CD8loT cell subsets of [@@@]\rmalpha [@@@]β T cells recognize antigens presented in MHC class II molecules, while the CD4−CD8+T cell subset recognizes antigens presented in MHC class I molecules. Porcine [@@@]\rmalpha [@@@]β T cells localize mainly in lymphoid tissues, whereas γδ T cells predominate in the blood and intestinal epithelium of pigs. Porcine CD8+[@@@]\rmalpha [@@@]β T cells are a prominent T-cell subset during antiviral responses, while porcine CD4+[@@@]\rmalpha [@@@]β T cell responses predominantly occur in bacterial and parasitic infections. Porcine γδ T cell responses have been reported in only a few infections. Porcine T cell responses are suppressed by some viruses and bacteria. The mechanisms of T cell suppression are not entirely known but reportedly include the killing of T cells, the inhibition of T cell activation and proliferation, the inhibition of antiviral cytokine production, and the induction of immunosuppressive cytokines.

scholarly journals Single-cell analysis reveals the origins and intrahepatic development of liver-resident IFN-γ-producing γδ T cells

2021 ◽  
Vol 18 (4) ◽  
pp. 954-968
Author(s):  
Yuan Hu ◽  
Keke Fang ◽  
Yanan Wang ◽  
Nan Lu ◽  
Haoyu Sun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Adoptive Transfer ◽  
Γδ T Cells ◽  
Developmental Trajectory ◽  
Γδ T Cell ◽  
Developmental Pathway ◽  
Hematopoietic Progenitor ◽  
Ifn Γ

Abstractγδ T cells are heterogeneous lymphocytes located in various tissues. However, a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved. In this study, we performed single-cell RNA sequencing (scRNA-seq) to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples. We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors (pre-γδ T cells). The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments. The adoptive transfer of hematopoietic progenitor Lin−Sca-1+Mac-1+ (LSM) cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma+ (IFN-γ+) but not interleukin-17a+ (IL-17a+) γδ T cells in the liver. Importantly, thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner. These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells, which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.

scholarly journals Critical role for Slam/SAP signaling in the thymic developmental programming of IL-17- and IFN-γ-producing γδ T cells

2019 ◽  
Author(s):  
Oliver Dienz ◽  
Victoria L. DeVault ◽  
Shawn C. Musial ◽  
Somen K. Mistri ◽  
Linda Mei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathway ◽  
Functional Programming ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
Thymic Development ◽  
Slam Family ◽  
Ifn Γ

AbstractDuring thymic development, γδ T cells commit to either an IFN-γ- or an IL-17-producing phenotype through mechanisms that remain unclear. Here, we investigated whether the SLAM/SAP signaling pathway played a role in the functional programming of thymic γδ T cells. Characterization of SLAM family receptor expression revealed that thymic γδ T cell subsets were each marked by distinct co-expression profiles of SLAMF1, SLAMF4, and SLAMF6. In the thymus, immature CD24hiVγ1 and Vγ4 γδ T cells were largely contained within a SLAMF1+SLAMF6+double positive (DP) population, while mature CD24lowsubsets were either SLAMF1+or SLAMF6+single positive (SP) cells. In the periphery, SLAMF1 and SLAMF6 expression on Vγ1, Vγ4, and Vγ6 T cells distinguished IL-17- and IFN-γ-producing subsets, respectively. Disruption of SLAM family receptor signaling through deletion of SAP resulted in impaired thymic γδ T cell maturation at the CD24hiSLAMF1+SLAMF6+DP stage that was associated with a decreased frequency of CD44+RORγt+γδ T cells. These defects were in turn associated with impaired γδ T cell IL-17 and IFN-γ production in both the thymus as well as in peripheral tissues. The role for SAP was subset-specific, as Vγ1, Vγ4, Vγ5, but not Vγ6 subsets were SAP-dependent. Together, these data suggest that the SLAM/SAP signaling pathway regulates a critical checkpoint in the functional programming of IL-17 and IFN-γ-producing γδ T cell subsets during thymic development.

scholarly journals γδ T Cells but Not NK Cells Are Essential for Cell-Mediated Immunity against Plasmodium chabaudi Malaria

2010 ◽  
Vol 78 (10) ◽  
pp. 4331-4340 ◽  
Author(s):  
William P. Weidanz ◽  
GayeLyn LaFleur ◽  
Andrew Brown ◽  
James M. Burns ◽  
Irene Gramaglia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Γδ T Cells ◽  
Cell Mediated Immunity ◽  
Γδ T Cell ◽  
Plasmodium Chabaudi ◽  
Ifn Γ ◽  
Time Courses

ABSTRACT Blood-stage Plasmodium chabaudi infections are suppressed by antibody-mediated immunity and/or cell-mediated immunity (CMI). To determine the contributions of NK cells and γδ T cells to protective immunity, C57BL/6 (wild-type [WT]) mice and B-cell-deficient (JH−/− ) mice were infected with P. chabaudi and depleted of NK cells or γδ T cells with monoclonal antibody. The time courses of parasitemia in NK-cell-depleted WT mice and JH−/− mice were similar to those of control mice, indicating that deficiencies in NK cells, NKT cells, or CD8+ T cells had little effect on parasitemia. In contrast, high levels of noncuring parasitemia occurred in JH−/− mice depleted of γδ T cells. Depletion of γδ T cells during chronic parasitemia in B-cell-deficient JH−/− mice resulted in an immediate and marked exacerbation of parasitemia, suggesting that γδ T cells have a direct killing effect in vivo on blood-stage parasites. Cytokine analyses revealed that levels of interleukin-10, gamma interferon (IFN-γ), and macrophage chemoattractant protein 1 (MCP-1) in the sera of γδ T-cell-depleted mice were significantly (P < 0.05) decreased compared to hamster immunoglobulin-injected controls, but these cytokine levels were similar in NK-cell-depleted mice and their controls. The time courses of parasitemia in CCR2−/− and JH−/− × CCR2−/− mice and in their controls were nearly identical, indicating that MCP-1 is not required for the control of parasitemia. Collectively, these data indicate that the suppression of acute P. chabaudi infection by CMI is γδ T cell dependent, is independent of NK cells, and may be attributed to the deficient IFN-γ response seen early in γδ T-cell-depleted mice.

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