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.

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.

Various Ages Thymus Transplantation Has Differential Ability of Anti Tumor Effects

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5799-5799
Author(s):  
Yuming Zhang ◽  
Xiaoqing Feng ◽  
Cuiling Wu ◽  
Wenling Guo ◽  
Huiping Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Size ◽  
Allogeneic Bone ◽  
Lymphocyte Function ◽  
Fetal Thymus ◽  
Cell Functions ◽  
Thymus Transplantation ◽  
Thymus Tissue ◽  
Ifn Γ

Abstract [Objective] Our previously work has demonstrated that allogeneic bone marrow transplantation (allo-BMT) combined with thymus transplantation (TT) was effective in restoring donor-derived T cell function and was beneficial for enhancing graft versus tumor (GVT) effects. However, since the thymic cell functions differ with age, the most effective age of thymus should be explored. In the present study, we examined the effects of allo-BMT plus thymus transplantation (TT) from various ages (fetal, newborn, adult) to determine it’s anti tumor effects. [Methods] BALB/c mice (H-2d ) bearing Meth-A sarcoma (H-2d )were treated with allo-BMT combined with or without TT from various age B6 mice(H-2b), the tumor size and survival period of the recipient BALB/c mice were examined, histological studies were performed in the liver, intestine, and the engrafted thymus from the recipients 4 weeks after the BMT. Surface markers on lymphocytes from the spleen were analyzed by 3-color fluorescence staining using a FACScan system to determine chimerism. Cytokine production was examined for monitoring lymphocyte function. [Results]. All mice treated with BMT with or without TT showed fully donor-derived chimerism. The tumor size were significantly smaller in the mice treated with BMT plus TT than those treated with BMT alone. Interestingly, the mice treated with BMT plus newborn or fetal thymus showed the greatest degree of tumor regression. The survival rate in mice treated with BMT plus newborn thymus was significantly prolonged compared with those treated with BMT plus adult thymus or BMT plus fetal thymus. Histologically, both the cortex and medullar areas were clearly shown in each group. Normal T-cell differentiation was also observed in the engrafted thymus. The number of CD4+ T cells significantly increased in the mice treated with BMT plus TT compared with those treated BMT alone. The numbers were highest in the mice treated with BMT plus newborn thymus or BMT plus fetal thymus. Microscopic founding of small intestine and liver indicated no evidence of GVHD in all mice treated with BMT combined with or without TT. The production of IL-2 and IFN-γ was significantly elevated in the mice treated with BMT plus TT compared with those treated with BMT alone. However, the production of IL-2 has no significantly difference in all various age thymus transplantation groups. In contrast, the production of IFN-γ was the highest in the mice treated with BMT plus newborn thymus transplantation. [Conclusion]. The present study indicated that allo-BMT combined with TT induces high thymopoiesis, elicit strong GVT effects, and is effective for the host with cancer. And the combination of allo-BMT with newborn thymus is the most effect. We thus found that donor-derived T cells play an important role in the treatment of leukemia. As human thymus tissue can be obtained from patient with congenital heart disease or from aborted fetuses, so the results of the present study suggest this strategy will become a new way for the treatment of malignant tumors in human. Disclosures No relevant conflicts of interest to declare.

Sustained Notch1 signaling instructs the earliest human intrathymic precursors to adopt a γδ T-cell fate in fetal thymus organ culture

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2444-2451 ◽  
Author(s):  
Marina García-Peydró ◽  
Virginia G. de Yébenes ◽  
María L. Toribio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Organ Culture ◽  
Cell Fate ◽  
Γδ T Cells ◽  
Retroviral Vectors ◽  
Γδ T Cell ◽  
Fetal Thymus ◽  
Notch1 Signaling ◽  
The Impact

Abstract Notch1 activity is essential for the specification of T-lineage fate in hematopoietic progenitors. Once the T-cell lineage is specified, T-cell precursors in the thymus must choose between αβ and γδ lineages. However, the impact of Notch1 signaling on intrathymic pro-T cells has not been addressed directly. To approach this issue, we used retroviral vectors to express constitutively active Notch1 in human thymocyte progenitors positioned at successive developmental stages, and we followed their differentiation in fetal thymus organ culture (FTOC). Here we show that sustained Notch1 signaling impairs progression to the double-positive (DP) stage and efficiently diverts the earliest thymic progenitors from the main αβ T-cell pathway toward development of γδ T cells. The impact of Notch1 signaling on skewed γδ production decreases progressively along intrathymic maturation and is restricted to precursor stages upstream of the pre-T-cell receptor checkpoint. Close to and beyond that point, Notch1 is not further able to instruct γδ cell fate, but promotes an abnormal expansion of αβ-committed thymocytes. These results stress the stage-specific impact of Notch1 signaling in intrathymic differentiation and suggest that regulation of Notch1 activity at defined developmental windows is essential to control αβ versus γδ T-cell development and to avoid deregulated expansion of αβ-lineage cells. (Blood. 2003;102:2444-2451)

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 < .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 < .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 < .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 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.

scholarly journals γδ-Thymocyte Maturation and Emigration

2021 ◽  
Author(s):  
K. Joannou ◽  
D.P. Golec ◽  
H. Wang ◽  
L.M. Henao-Caviedes ◽  
J.F. May ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Γδ T Cells ◽  
Cell Development ◽  
Γδ T Cell ◽  
Fetal Thymus ◽  
Adult Mice ◽  
The Relationship ◽  
Adult Thymus

AbstractThe thymus is the site of both αβ and γδ-T cell development. After several unique waves of γδ-T cells are generated in, and exported from, the fetal/neonatal thymus, the adult thymus continues to produce a stream of γδ-T cells throughout life. One intriguing feature of γδ T cell development is the coordination of differentiation and acquisition of effector function within the fetal thymus, however, it is less clear whether this paradigm holds true in adult animals. To investigate the relationship between maturation and time since V(D)J recombination in adult-derived γδ-thymocytes, we used the Rag2pGFP model. Immature (CD24+) γδ-thymocytes expressed high levels of GFP while only a small minority of mature (CD24-) γδ-thymocytes were GFP+. Similarly, most GFP+ γδ-splenocytes were immature, while some were mature. Analysis of γδ-recent thymic emigrants (RTEs) indicated that most γδ-T cell RTEs were CD24+ and GFP+ and adoptive transfer experiments showed that immature γδ-thymocytes could be maintained in the periphery for at least 3 days over which time they matured. With respect to the mature γδ-thymocytes that were GFP-, parabiosis experiments demonstrated that mature γδ-T cells did not recirculate from the periphery. Instead, a population of mature γδ-thymocytes remained resident in the thymus for at least 60 days while mature γδ-thymocytes derived solely from adult hematopoiesis were mostly lost from the thymus within 60 days. Collectively, these data demonstrate two streams of actively developing γδ-T cells in adult mice: an immature subset that quickly leaves the thymus and matures in the periphery, and one that completes maturation within the thymus over a longer period of time. Furthermore, there is a fetal-derived and heterogeneous population of resident γδ-thymocytes of unknown functional importance.

scholarly journals Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 713 ◽  
Author(s):  
Ruben Serrano ◽  
Daniela Wesch ◽  
Dieter Kabelitz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Zoledronic Acid ◽  
T Cell Activation ◽  
Cell Activation ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Toll Like Receptor ◽  
Tnf Α ◽  
Ifn Γ

Background: Human Vγ9Vδ2 γδ T cells can kill a variety of cancer cells and have attracted substantial interest for cancer immunotherapy. Toll-like receptor (TLR) ligands are promising adjuvants for cancer immunotherapy, but TLR7/8 ligand Resiquimod has been shown to inhibit CD4 T-cell activation in a monocyte-dependent manner. Therefore, we studied the modulation of human γδ T-cell activation by TLR7/8 ligands. Methods: Peripheral blood mononuclear cells (PBMC) or purified γδ T cells together with purified monocytes were stimulated with zoledronic acid or phosphoantigens in the absence or presence of various imidazoquinoline TLR7 or TLR8 agonists. Read-out systems included interferon-γ induction and cellular expansion of γδ T cells, as well as viability, cell surface antigen modulation, and IL-1β and TNF-α production of monocytes. Results: TLR8 ligand TL8-506 and TLR7/8 ligand Resiquimod (but not TLR7 ligands) rapidly induced IFN-γ expression in γδ T cells within PBMC, and co-stimulated phosphoantigen-induced IFN-γ expression in γδ T cells. On the other hand, TLR8 ligands potently suppressed γδ T-cell expansion in response to zoledronic acid and phosphoantigen. Purified monocytes secreted large amounts of IL-1β and TNF-α when stimulated with TLR8 ligands but simultaneously underwent substantial cell death after 24 h. Conclusions: TLR8 ligand-activated monocytes potently co-stimulate early γδ T-cell activation but failed to provide accessory cell function for in vitro expansion of γδ T cells.

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.

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