scholarly journals Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology

2018 ◽  
Vol 115 (5) ◽  
pp. 1039-1044 ◽  
Author(s):  
Pierre Vantourout ◽  
Adam Laing ◽  
Martin J. Woodward ◽  
Iva Zlatareva ◽  
Luis Apolonia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
Human Peripheral Blood ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Γδ T Cell ◽  
Human Gut ◽  
Peripheral Tissues ◽  
T Cell Biology

The long-held view that gamma delta (γδ) T cells in mice and humans are fundamentally dissimilar, as are γδ cells in blood and peripheral tissues, has been challenged by emerging evidence of the cells’ regulation by butyrophilin (BTN) and butyrophilin-like (BTNL) molecules. Thus, murine Btnl1 and the related gene, Skint1, mediate T cell receptor (TCR)-dependent selection of murine intraepithelial γδ T cell repertoires in gut and skin, respectively; BTNL3 and BTNL8 are TCR-dependent regulators of human gut γδ cells; and BTN3A1 is essential for TCR-dependent activation of human peripheral blood Vγ9Vδ2+ T cells. However, some observations concerning BTN/Btnl molecules continue to question the extent of mechanistic conservation. In particular, murine and human gut γδ cell regulation depends on pairings of Btnl1 and Btnl6 and BTNL3 and BTNL8, respectively, whereas blood γδ cells are reported to be regulated by BTN3A1 independent of other BTNs. Addressing this paradox, we show that BTN3A2 regulates the subcellular localization of BTN3A1, including functionally important associations with the endoplasmic reticulum (ER), and is specifically required for optimal BTN3A1-mediated activation of Vγ9Vδ2+ T cells. Evidence that BTNL3/BTNL8 and Btnl1/Btnl6 likewise associate with the ER reinforces the prospect of broadly conserved mechanisms underpinning the selection and activation of γδ cells in mice and humans, and in blood and extralymphoid sites.

scholarly journals T Cell Receptor Specificity Is Critical for the Development of Epidermal γδ T Cells

2001 ◽  
Vol 194 (10) ◽  
pp. 1473-1483 ◽  
Author(s):  
Isabel Ferrero ◽  
Anne Wilson ◽  
Friedrich Beermann ◽  
Werner Held ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Wild Type ◽  
Normal Numbers ◽  
T Cell Biology

A particular feature of γδ T cell biology is that cells expressing T cell receptor (TCR) using specific Vγ/Vδ segments are localized in distinct epithelial sites, e.g., in mouse epidermis nearly all γδ T cells express Vγ3/Vδ1. These cells, referred to as dendritic epidermal T cells (DETC) originate from fetal Vγ3+ thymocytes. The role of γδ TCR specificity in DETC's migration/localization to the skin has remained controversial. To address this issue we have generated transgenic (Tg) mice expressing a TCR δ chain (Vδ6.3-Dδ1-Dδ2-Jδ1-Cδ), which can pair with Vγ3 in fetal thymocytes but is not normally expressed by DETC. In wild-type (wt) Vδ6.3Tg mice DETC were present and virtually all of them express Vδ6.3. However, DETC were absent in TCR-δ−/− Vδ6.3Tg mice, despite the fact that Vδ6.3Tg γδ T cells were present in normal numbers in other lymphoid and nonlymphoid tissues. In wt Vδ6.3Tg mice, a high proportion of in-frame Vδ1 transcripts were found in DETC, suggesting that the expression of an endogenous TCR-δ (most probably Vδ1) was required for the development of Vδ6.3+ epidermal γδ T cells. Collectively our data demonstrate that TCR specificity is essential for the development of γδ T cells in the epidermis. Moreover, they show that the TCR-δ locus is not allelically excluded.

scholarly journals The Unknown Unknowns: Recovering Gamma-Delta T Cells for Control of Human Immunodeficiency Virus (HIV)

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1455
Author(s):  
Shivkumar Biradar ◽  
Michael T. Lotze ◽  
Robbie B. Mailliard
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
T Cell Biology ◽  
Immunodeficiency Virus

Recent advances in γδ T cell biology have focused on the unique attributes of these cells and their role in regulating innate and adaptive immunity, promoting tissue homeostasis, and providing resistance to various disorders. Numerous bacterial and viral pathogens, including human immunodeficiency virus-1 (HIV), greatly alter the composition of γδ T cells in vivo. Despite the effectiveness of antiretroviral therapy (ART) in controlling HIV and restoring health in those affected, γδ T cells are dramatically impacted during HIV infection and fail to reconstitute to normal levels in HIV-infected individuals during ART for reasons that are not clearly understood. Importantly, their role in controlling HIV infection, and the implications of their failure to rebound during ART are also largely unknown and understudied. Here, we review important aspects of human γδ T cell biology, the effector and immunomodulatory properties of these cells, their prevalence and function in HIV, and their immunotherapeutic potential.

scholarly journals Our evolving understanding of the role of the γδ T cell receptor in γδ T cell mediated immunity

2021 ◽  
Author(s):  
Benjamin S. Gully ◽  
Jamie Rossjohn ◽  
Martin S. Davey
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Structural Basis ◽  
Cell Mediated Immunity ◽  
Γδ T Cell ◽  
T Cell Biology ◽  
Γδ T Cell Receptor

The γδ T cell immune cell lineage has remained relatively enigmatic and under-characterised since their identification. Conversely, the insights we have, highlight their central importance in diverse immunological roles and homeostasis. Thus, γδ T cells are considered as potentially a new translational tool in the design of new therapeutics for cancer and infectious disease. Here we review our current understanding of γδ T cell biology viewed through a structural lens centred on the how the γδ T cell receptor mediates ligand recognition. We discuss the limited knowledge of antigens, the structural basis of such reactivities and discuss the emerging trends of γδ T cell reactivity and implications for γδ T cell biology.

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 Activation-induced Modification in the CD3 Complex of the γδ T Cell Receptor

2002 ◽  
Vol 196 (10) ◽  
pp. 1355-1361 ◽  
Author(s):  
Sandra M. Hayes ◽  
Karen Laky ◽  
Dalal El-Khoury ◽  
Dietmar J. Kappes ◽  
B.J. Fowlkes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Subunit Composition ◽  
Γδ T Cell ◽  
Receptor Complexes ◽  
Functional Consequences

The T cell antigen receptor complexes expressed on αβ and γδ T cells differ not only in their respective clonotypic heterodimers but also in the subunit composition of their CD3 complexes. The γδ T cell receptors (TCRs) expressed on ex vivo γδ T cells lack CD3δ, whereas αβ TCRs contain CD3δ. While this result correlates with the phenotype of CD3δ−/− mice, in which γδ T cell development is unaffected, it is inconsistent with the results of previous studies reporting that CD3δ is a component of the γδ TCR. Since earlier studies examined the subunit composition of γδ TCRs expressed on activated and expanded peripheral γδ T cells or γδ TCR+ intestinal intraepithelial lymphocytes, we hypothesized that activation and expansion may lead to changes in the CD3 subunit composition of the γδ TCR. Here, we report that activation and expansion do in fact result in the inclusion of a protein, comparable in mass and mobility to CD3δ, in the γδ TCR. Further analyses revealed that this protein is not CD3δ, but instead is a differentially glycosylated form of CD3γ. These results provide further evidence for a major difference in the subunit composition of αβ- and γδ TCR complexes and raise the possibility that modification of CD3γ may have important functional consequences in activated γδ T cells.

scholarly journals Phospholipase Cγ1 is essential for T cell development, activation, and tolerance

2010 ◽  
Vol 207 (2) ◽  
pp. 309-318 ◽  
Author(s):  
Guoping Fu ◽  
Yuhong Chen ◽  
Mei Yu ◽  
Andy Podd ◽  
James Schuman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Phospholipase Cγ1 ◽  
T Cell Biology ◽  
Single Positive ◽  
And Function

Phospholipase Cγ1 (PLCγ1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCγ1 in T cell biology, we generated and examined mice with T cell–specific deletion of PLCγ1. We demonstrate that PLCγ1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-κB. Importantly, PLCγ1 deficiency impairs the development and function of FoxP3+ regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLCγ1 is essential for T cell development, activation, and tolerance.

scholarly journals Splenic γδ T Cells Regulated by CD4+ T Cells Are Required To Control Chronic Plasmodium chabaudi Malaria in the B-Cell-Deficient Mouse

2006 ◽  
Vol 74 (5) ◽  
pp. 2717-2725 ◽  
Author(s):  
Henri C. van der Heyde ◽  
Joan M. Batchelder ◽  
Matyas Sandor ◽  
William P. Weidanz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Blood Stage ◽  
Cell Mediated Immunity ◽  
Γδ T Cell ◽  
Plasmodium Chabaudi ◽  
Antibody Treatment ◽  
Time Courses

ABSTRACT Little is known about the function and regulation of splenic γδ T cells during chronic Plasmodium chabaudi malaria. The splenic γδ T-cell population continues to expand, reaching levels equal to 4 times the number of splenocytes in an uninfected mouse. Splenic γδ T cells from JH −/− mice with chronic malaria expressed Vγ1+ or Vδ4+ in the same ratio as uninfected controls with Vγ1 cells dominating, but the Vγ2 ratio declined about twofold. γδ T cells from G8 mice specific for the TL antigen increased only 2-fold in number, compared with 10-fold in BALB/c controls, but G8 γδ T cells failed to express the B220 activation marker. Elimination of the parasite by drug treatment caused a slow depletion in the number of splenic γδ, CD4+, and CD8+ T cells. Following challenge, drug-cured JH −/− mice exhibited nearly identical parasitemia time courses as naïve controls. Depletion of either CD4+ T cells or γδ T cells from chronically infected JH −/− mice by monoclonal antibody treatment resulted in an immediate and significant (P < 0.05) exacerbation of parasitemia coupled with a marked decrease in splenic γδ T-cell numbers. The number of CD4+ T cells, in contrast, did not decrease in mice after anti-T-cell receptor γδ treatment. The results indicate that cell-mediated immunity against blood-stage malarial parasites during chronic malaria (i) requires the continued presence of blood-stage parasites to remain functional, (ii) is dependent upon both γδ T cells and CD4+ T cells, and (iii) lacks immunological memory.

scholarly journals Enhanced development of CD4+ γδ T cells in the absence of Itk results in elevated IgE production

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 564-571 ◽  
Author(s):  
Qian Qi ◽  
Mingcan Xia ◽  
Jianfang Hu ◽  
Elizabeth Hicks ◽  
Archana Iyer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Th2 Cells ◽  
Th2 Cytokines ◽  
Γδ T Cell ◽  
Histocompatibility Complex ◽  
And Function ◽  
Deficient Mice

AbstractThe Tec kinase Itk is critical for the development of αβ T cells as well as differentiation of CD4+ T cells into Th2 cells. Itk null mice have defects in the production of Th2 cytokines; however, they paradoxically have significant elevations in serum IgE. Here we show that Itk null mice have increased numbers of γδ T cells in the thymus and spleen. This includes elevated numbers of CD4+ γδ T cell, the majority of which carry the Vγ1.1 and Vδ6.2/3 γδ T-cell receptor with a distinct phenotype. The development of these CD4+ γδ T cells is T cell intrinsic, independent of either major histocompatibility complex class I or class II, and is favored during development in the absence of Itk. Itk null CD4+ γδ T cells secrete significant amounts of Th2 cytokines and can induce the secretion of IgE by wild-type B cells. Our data indicate that Itk plays important role in regulating γδ T-cell development and function. In addition, our data indicate that the elevated IgE observed in Itk-deficient mice is due in part to the enhanced development of CD4+ γδ T cells in the absence of Itk.

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.

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