scholarly journals Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

2015 ◽  
Vol 112 (6) ◽  
pp. E556-E565 ◽  
Author(s):  
Tanya Dimova ◽  
Margreet Brouwer ◽  
Françoise Gosselin ◽  
Joël Tassignon ◽  
Oberdan Leo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
Γδ T Cells ◽  
Variable Region ◽  
Chain Gene ◽  
Γδ T Cell ◽  
Fetal Blood ◽  
Microbial Exposure ◽  
Vγ9vδ2 T Cells

γδ T cells are unconventional T cells recognizing antigens via their γδ T-cell receptor (TCR) in a way that is fundamentally different from conventional αβ T cells. γδ T cells usually are divided into subsets according the type of Vγ and/or Vδ chain they express in their TCR. T cells expressing the TCR containing the γ-chain variable region 9 and the δ-chain variable region 2 (Vγ9Vδ2 T cells) are the predominant γδ T-cell subset in human adult peripheral blood. The current thought is that this predominance is the result of the postnatal expansion of cells expressing particular complementary-determining region 3 (CDR3) in response to encounters with microbes, especially those generating phosphoantigens derived from the 2-C-methyl-d-erythritol 4-phosphate pathway of isoprenoid synthesis. However, here we show that, rather than requiring postnatal microbial exposure, Vγ9Vδ2 T cells are the predominant blood subset in the second-trimester fetus, whereas Vδ1+ and Vδ3+ γδ T cells are present only at low frequencies at this gestational time. Fetal blood Vγ9Vδ2 T cells are phosphoantigen responsive and display very limited diversity in the CDR3 of the Vγ9 chain gene, where a germline-encoded sequence accounts for >50% of all sequences, in association with a prototypic CDR3δ2. Furthermore, these fetal blood Vγ9Vδ2 T cells are functionally preprogrammed (e.g., IFN-γ and granzymes-A/K), with properties of rapidly activatable innatelike T cells. Thus, enrichment for phosphoantigen-responsive effector T cells has occurred within the fetus before postnatal microbial exposure. These various characteristics have been linked in the mouse to the action of selecting elements and would establish a much stronger parallel between human and murine γδ T cells than is usually articulated.

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.

scholarly journals Microbial exposure drives polyclonal expansion of innate γδ T cells immediately after birth

2020 ◽  
Vol 117 (31) ◽  
pp. 18649-18660 ◽  
Author(s):  
Sarina Ravens ◽  
Alina S. Fichtner ◽  
Maike Willers ◽  
Dennis Torkornoo ◽  
Sabine Pirr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
Sub Saharan Africa ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
Microbial Exposure ◽  
Sub Saharan ◽  
Next Generation Sequencing Ngs ◽  
Infants And Young Children

Starting at birth, the immune system of newborns and children encounters and is influenced by environmental challenges. It is still not completely understood how γδ T cells emerge and adapt during early life. Studying the composition of T cell receptors (TCRs) using next-generation sequencing (NGS) in neonates, infants, and children can provide valuable insights into the adaptation of T cell subsets. To investigate how neonatal γδ T cell repertoires are shaped by microbial exposure after birth, we monitored the γ-chain (TRG) and δ-chain (TRD) repertoires of peripheral blood T cells in newborns, infants, and young children from Europe and sub-Saharan Africa. We identified a set ofTRGandTRDsequences that were shared by all children from Europe and Africa. These were primarily public clones, characterized by simple rearrangements of Vγ9 and Vδ2 chains with low junctional diversity and usage of non-TRDJ1gene segments, reminiscent of early ontogenetic subsets of γδ T cells. Further profiling revealed that these innate, public Vγ9Vδ2+T cells underwent an immediate TCR-driven polyclonal proliferation within the first 4 wk of life. In contrast, γδ T cells using Vδ1+and Vδ3+TRDrearrangements did not significantly expand after birth. However, different environmental cues may lead to the observed increase of Vδ1+and Vδ3+TRDsequences in the majority of African children. In summary, we show how dynamic γδ TCR repertoires develop directly after birth and present important differences among γδ T cell subsets.

scholarly journals Control of Plasmodium falciparum erythrocytic cycle: γδ T cells target the red blood cell–invasive merozoites

Blood ◽  
2011 ◽  
Vol 118 (26) ◽  
pp. 6952-6962 ◽  
Author(s):  
Giulia Costa ◽  
Séverine Loizon ◽  
Marianne Guenot ◽  
Iulia Mocan ◽  
Franck Halary ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
T Cell ◽  
Blood Cell ◽  
Parasite Density ◽  
Red Blood Cell ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Antiparasitic Activity ◽  
Vγ9vδ2 T Cells

AbstractThe control of Plasmodium falciparum erythrocytic parasite density is essential for protection against malaria, because it prevents pathogenesis and progression toward severe disease. P falciparum blood-stage parasite cultures are inhibited by human Vγ9Vδ2 γδ T cells, but the underlying mechanism remains poorly understood. Here, we show that both intraerythrocytic parasites and the extracellular red blood cell–invasive merozoites specifically activate Vγ9Vδ2 T cells in a γδ T cell receptor–dependent manner and trigger their degranulation. In contrast, the γδ T cell–mediated antiparasitic activity only targets the extracellular merozoites. Using perforin-deficient and granulysin-silenced T-cell lines, we demonstrate that granulysin is essential for the in vitro antiplasmodial process, whereas perforin is dispensable. Patients infected with P falciparum exhibited elevated granulysin plasma levels associated with high levels of granulysin-expressing Vδ2+ T cells endowed with parasite-specific degranulation capacity. This indicates in vivo activation of Vγ9Vδ2 T cells along with granulysin triggering and discharge during primary acute falciparum malaria. Altogether, this work identifies Vγ9Vδ2 T cells as unconventional immune effectors targeting the red blood cell–invasive extracellular P falciparum merozoites and opens novel perspectives for immune interventions harnessing the antiparasitic activity of Vγ9Vδ2 T cells to control parasite density in malaria patients.

scholarly journals Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2269-2279 ◽  
Author(s):  
Christelle Harly ◽  
Yves Guillaume ◽  
Steven Nedellec ◽  
Cassie-Marie Peigné ◽  
Hannu Mönkkönen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Subset ◽  
Cell Receptor ◽  
Causal Link ◽  
Target Cells ◽  
Γδ T Cell ◽  
Vγ9vδ2 T Cells

Abstract Human peripheral Vγ9Vδ2 T cells are activated by phosphorylated metabolites (phosphoagonists [PAg]) of the mammalian mevalonate or the microbial desoxyxylulose-phosphate pathways accumulated by infected or metabolically distressed cells. The underlying mechanisms are unknown. We show that treatment of nonsusceptible target cells with antibody 20.1 against CD277, a member of the extended B7 superfamily related to butyrophilin, mimics PAg-induced Vγ9Vδ2 T-cell activation and that the Vγ9Vδ2 T-cell receptor is implicated in this effect. Vγ9Vδ2 T-cell activation can be abrogated by exposing susceptible cells (tumor and mycobacteria-infected cells, or aminobisphosphonate-treated cells with up-regulated PAg levels) to antibody 103.2 against CD277. CD277 knockdown and domain-shuffling approaches confirm the key implication of the CD277 isoform BTN3A1 in PAg sensing by Vγ9Vδ2 T cells. Fluorescence recovery after photobleaching (FRAP) experiments support a causal link between intracellular PAg accumulation, decreased BTN3A1 membrane mobility, and ensuing Vγ9Vδ2 T-cell activation. This study demonstrates a novel role played by B7-like molecules in human γδ T-cell antigenic activation and paves the way for new strategies to improve the efficiency of immunotherapies using Vγ9Vδ2 T cells.

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 Mechanisms underlying γδ T-cell subset perturbations in SIV-infected Asian rhesus macaques

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4148-4157 ◽  
Author(s):  
Levelle D. Harris ◽  
Nichole R. Klatt ◽  
Carol Vinton ◽  
Judith A. Briant ◽  
Brian Tabb ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Rhesus Macaques ◽  
Cell Subset ◽  
Γδ T Cells ◽  
Microbial Translocation ◽  
Therapeutic Interventions ◽  
Γδ T Cell ◽  
Gastrointestinal Mucosa

Abstract T cells that express the γδ T-cell receptor, which recognize microbial or stress-induced antigens, represent a minority of blood T cells but constitute a major proportion of intraepithelial lymphocytes in the gastrointestinal mucosa. As microbial products have been shown to translocate from the gastrointestinal tract into circulation in chronically HIV/Simian immunodeficiency virus (SIV)–infected individuals, we conducted a study of Vδ1 and Vδ2 T-cell frequency, phenotype, and function in blood, spleen, lymph nodes, gastrointestinal mucosa, and bronchoalveolar lavage of uninfected and chronically SIVsmE543-infected rhesus macaques (RMs). We found: (1) SIV-associated inversion of Vδ1/Vδ2 T cells occurs in blood and in several tissues; (2) γδ T cells are not infected by SIV in vivo; (3) the Vδ1/Vδ2 inversion involves expansion of Vδ1 T cells; (4) expanded Vδ1 T cells are phenotypically and functionally different from Vδ1 T cells from uninfected RMs; and (5) the stimulus underlying expansion of Vδ1 T cells appears to be microbial translocation. These data highlight the importance of microbial translocation–induced immune activation in chronically infected individuals and provide new insights into an immune dysregulation phenomenon that is a hallmark of HIV/SIV infection. These findings may lead to novel therapeutic interventions that improve the immune responses against microbial antigens, and thus, decrease microbial translocation–induced im-mune activation.

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 Alpaca (Vicugna pacos), the first nonprimate species with a phosphoantigen-reactive Vγ9Vδ2 T cell subset

2020 ◽  
Vol 117 (12) ◽  
pp. 6697-6707 ◽  
Author(s):  
Alina S. Fichtner ◽  
Mohindar M. Karunakaran ◽  
Siyi Gu ◽  
Christopher T. Boughter ◽  
Marta T. Borowska ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Molecular Mechanisms ◽  
Mammalian Species ◽  
Cell Subset ◽  
Γδ T Cells ◽  
Vicugna Pacos ◽  
A Genome ◽  
Vγ9vδ2 T Cells

Vγ9Vδ2 T cells are a major γδ T cell population in the human blood expressing a characteristic Vγ9JP rearrangement paired with Vδ2. This cell subset is activated in a TCR-dependent and MHC-unrestricted fashion by so-called phosphoantigens (PAgs). PAgs can be microbial [(E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, HMBPP] or endogenous (isopentenyl pyrophosphate, IPP) and PAg sensing depends on the expression of B7-like butyrophilin (BTN3A, CD277) molecules. IPP increases in some transformed or aminobisphosphonate-treated cells, rendering those cells a target for Vγ9Vδ2 T cells in immunotherapy. Yet, functional Vγ9Vδ2 T cells have only been described in humans and higher primates. Using a genome-based study, we showed in silico translatable genes encoding Vγ9, Vδ2, and BTN3 in a few nonprimate mammalian species. Here, with the help of new monoclonal antibodies, we directly identified a T cell population in the alpaca (Vicugna pacos), which responds to PAgs in a BTN3-dependent fashion and shows typicalTRGV9- andTRDV2-like rearrangements. T cell receptor (TCR) transductants andBTN3-deficient human 293T cells reconstituted with alpaca or human BTN3 or alpaca/human BTN3 chimeras showed that alpaca Vγ9Vδ2 TCRs recognize PAg in the context of human and alpaca BTN3. Furthermore, alpaca BTN3 mediates PAg recognition much better than human BTN3A1 alone and this improved functionality mapped to the transmembrane/cytoplasmic part of alpaca BTN3. In summary, we found remarkable similarities but also instructive differences of PAg-recognition by human and alpaca, which help in better understanding the molecular mechanisms controlling the activation of this prominent population of γδ T cells.

scholarly journals Assembly of Productive T Cell Receptor δ Variable Region Genes Exhibits Allelic Inclusion

1998 ◽  
Vol 188 (8) ◽  
pp. 1465-1471 ◽  
Author(s):  
Barry P. Sleckman ◽  
Bernard Khor ◽  
Robert Monroe ◽  
Frederick W. Alt
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Γδ T Cells ◽  
Variable Region ◽  
Cell Receptor ◽  
Allelic Exclusion ◽  
Γδ T Cell ◽  
Variable Regions ◽  
Variable Region Genes

The generation of a productive “in-frame” T cell receptor β (TCR β), immunoglobulin (Ig) heavy (H) or Ig light (L) chain variable region gene can result in the cessation of rearrangement of the alternate allele, a process referred to as allelic exclusion. This process ensures that most αβ T cells express a single TCR β chain and most B cells express single IgH and IgL chains. Assembly of TCR α and TCR γ chain variable region genes exhibit allelic inclusion and αβ and γδ T cells can express two TCR α or TCR γ chains, respectively. However, it was not known whether assembly of TCR δ variable regions genes is regulated in the context of allelic exclusion. To address this issue, we have analyzed TCR δ rearrangements in a panel of mouse splenic γδ T cell hybridomas. We find that, similar to TCR α and γ variable region genes, assembly of TCR δ variable region genes exhibits properties of allelic inclusion. These findings are discussed in the context of γδ T cell development and regulation of rearrangement of TCR δ genes.

scholarly journals β2 Integrins differentially regulate γδ T cell subset thymic development and peripheral maintenance

2020 ◽  
Vol 117 (36) ◽  
pp. 22367-22377
Author(s):  
Claire L. McIntyre ◽  
Leticia Monin ◽  
Jesse C. Rop ◽  
Thomas D. Otto ◽  
Carl S. Goodyear ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Cell Subset ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
Thymic Development ◽  
T Cell Subset

The γδ T cells reside predominantly at barrier sites and play essential roles in immune protection against infection and cancer. Despite recent advances in the development of γδ T cell immunotherapy, our understanding of the basic biology of these cells, including how their numbers are regulated in vivo, remains poor. This is particularly true for tissue-resident γδ T cells. We have identified the β2family of integrins as regulators of γδ T cells. β2-integrin–deficient mice displayed a striking increase in numbers of IL-17–producing Vγ6Vδ1+γδ T cells in the lungs, uterus, and circulation. Thymic development of this population was normal. However, single-cell RNA sequencing revealed the enrichment of genes associated with T cell survival and proliferation specifically in β2-integrin–deficient IL-17+cells compared to their wild-type counterparts. Indeed, β2-integrin–deficient Vγ6+cells from the lungs showed reduced apoptosis ex vivo, suggesting that increased survival contributes to the accumulation of these cells in β2-integrin–deficient tissues. Furthermore, our data revealed an unexpected role for β2integrins in promoting the thymic development of the IFNγ-producing CD27+Vγ4+γδ T cell subset. Together, our data reveal that β2integrins are important regulators of γδ T cell homeostasis, inhibiting the survival of IL-17–producing Vγ6Vδ1+cells and promoting the thymic development of the IFNγ-producing Vγ4+subset. Our study introduces unprecedented mechanisms of control for γδ T cell subsets.

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