Role of αβ and γδ T Cells in the Host Response toSalmonella Infection as Demonstrated in T-Cell-Receptor-Deficient Mice of Defined Ity Genotypes

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.

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Donor γδ T Lymphocytes Promote Allogeneic Engraftment Across the Major Histocompatibility Barrier in Mice

Blood ◽

10.1182/blood.v89.3.1100 ◽

1997 ◽

Vol 89 (3) ◽

pp. 1100-1109 ◽

Cited By ~ 34

Author(s):

William R. Drobyski ◽

David Majewski

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Γδ T Cells ◽

Cell Receptor ◽

Marrow Graft ◽

Hematopoietic Reconstitution ◽

Donor T Cells ◽

Αβ T Cells

Abstract T cells that express the αβ T-cell receptor are thought to be the T-cell population primarily responsible for facilitating alloengraftment. The role of γδ+ T cells that comprise only a minority of mature T cells in promoting allogeneic engraftment, however, has not been extensively studied. The purpose of this study was to determine whether γδ T cells were capable of facilitating alloengraftment in murine recipients of major histocompatibility complex-mismatched marrow grafts. We developed a model where engraftment of C57BL/6 × 129/F2 (H-2b) marrow in sublethally irradiated (800 cGy) recipients (AKR/J, H-2k) is dependent on the presence of mature donor T cells in the marrow graft. In this model, donor T-cell engraftment was significantly augmented by as few as 1 × 105 αβ T cells. The role of γδ T cells was then investigated using transgenic donors (C57BL/6 × 129 background) in which a portion of the T-cell receptor–β chain gene was deleted by gene targeting so that these mice lack αβ T cells. Addition of 10 × 106 naive γδ T cells to T-cell depleted marrow grafts was required to significantly increase alloengraftment, although donor T cells averaged <50% of total splenic T cells. To determine whether higher doses of γδ T cells would improve donor engraftment and eradicate residual host T cells, γδ T cells were ex vivo expanded with a γδ T-cell–specific monoclonal antibody and interleukin-2 and then transplanted into irradiated recipients. Transplantation of ≥ 160 × 106 activated γδ T cells was necessary to consistently and significantly augment donor cell chimerism and enhance hematopoietic reconstitution when compared to control mice, but host T cells persisted in these chimeras. Addition of 2.5 × 104 mature αβ T cells, which alone were incapable of facilitating engraftment, to T-cell depleted marrow grafts containing 160 × 106 activated γδ T cells resulted in long-term (<100 day) complete donor engraftment, indicating that limiting numbers of αβ T cells were required in the marrow graft for the eradication of residual host T cells. Using serial weight curves and B-cell reconstitution as end points, clinically significant graft-versus-host disease was not observed in these chimeras under these experimental conditions. These data show that, whereas less potent than αβ T cells, γδ T cells are able to promote engraftment and enhance hematopoietic reconstitution in allogeneic marrow transplant recipients.

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Immunosurveillance by human γδ T lymphocytes: the emerging role of butyrophilins

F1000Research ◽

10.12688/f1000research.11057.1 ◽

2017 ◽

Vol 6 ◽

pp. 782 ◽

Cited By ~ 10

Author(s):

Dieter Kabelitz ◽

Marcus Lettau ◽

Ottmar Janssen

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocytes ◽

T Cell Receptor ◽

T Cell Activation ◽

Γδ T Cells ◽

Cellular Transformation ◽

Cell Receptor ◽

Γδ T Cell

In contrast to conventional T lymphocytes, which carry an αβ T-cell receptor and recognize antigens as peptides presented by major histocompatibility complex class I or class II molecules, human γδ T cells recognize different metabolites such as non-peptidic pyrophosphate molecules that are secreted by microbes or overproduced by tumor cells. Hence, γδ T cells play a role in immunosurveillance of infection and cellular transformation. Until recently, it has been unknown how the γδ T-cell receptor senses such pyrophosphates in the absence of known antigen-presenting molecules. Recent studies from several groups have identified a unique role of butyrophilin (BTN) protein family members in this process, notably of BTN3A1. BTNs are a large family of transmembrane proteins with diverse functions in lipid secretion and innate and adaptive immunity. Here we discuss current models of how BTN molecules regulate γδ T-cell activation. We also address the implications of these recent findings on the design of novel immunotherapeutic strategies based on the activation of γδ T cells.

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Different composition of the human and the mouse γδ T cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficiencies

Journal of Experimental Medicine ◽

10.1084/jem.20070782 ◽

2007 ◽

Vol 204 (11) ◽

pp. 2537-2544 ◽

Cited By ~ 39

Author(s):

Gabrielle M. Siegers ◽

Mahima Swamy ◽

Edgar Fernández-Malavé ◽

Susana Minguet ◽

Sylvia Rathmann ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

T Cell Development ◽

Γδ T Cells ◽

Cell Receptor ◽

Cell Development ◽

Γδ T Cell ◽

Deficient Mice ◽

Γδ T Cell Receptor

The γδ T cell receptor for antigen (TCR) comprises the clonotypic TCRγδ, the CD3 (CD3γε and/or CD3δε), and the ζζ dimers. γδ T cells do not develop in CD3γ-deficient mice, whereas human patients lacking CD3γ have abundant peripheral blood γδ T cells expressing high γδ TCR levels. In an attempt to identify the molecular basis for these discordant phenotypes, we determined the stoichiometries of mouse and human γδ TCRs using blue native polyacrylamide gel electrophoresis and anti-TCR–specific antibodies. The γδ TCR isolated in digitonin from primary and cultured human γδ T cells includes CD3δ, with a TCRγδCD3ε2δγζ2 stoichiometry. In CD3γ-deficient patients, this may allow substitution of CD3γ by the CD3δ chain and thereby support γδ T cell development. In contrast, the mouse γδ TCR does not incorporate CD3δ and has a TCRγδCD3ε2γ2ζ2 stoichiometry. CD3γ-deficient mice exhibit a block in γδ T cell development. A human, but not a mouse, CD3δ transgene rescues γδ T cell development in mice lacking both mouse CD3δ and CD3γ chains. This suggests important structural and/or functional differences between human and mouse CD3δ chains during γδ T cell development. Collectively, our results indicate that the different γδ T cell phenotypes between CD3γ-deficient humans and mice can be explained by differences in their γδ TCR composition.

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Crucial role of the pre-T-cell receptor α gene in development of ap but not γδ T cells

Nature ◽

10.1038/375795a0 ◽

1995 ◽

Vol 375 (6534) ◽

pp. 795-798 ◽

Cited By ~ 361

Author(s):

Hans Jörg Fehling ◽

Anna Krotkova ◽

Claude Saint-Ruf ◽

Harald von Boehmer

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Crucial Role ◽

Γδ T Cells ◽

Cell Receptor

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Resistance of T-Cell Receptor δ-Chain-Deficient Mice to Experimental Candidaalbicans Vaginitis

Infection and Immunity ◽

10.1128/iai.69.11.7162-7164.2001 ◽

2001 ◽

Vol 69 (11) ◽

pp. 7162-7164 ◽

Cited By ~ 41

Author(s):

Floyd L. Wormley ◽

Chad Steele ◽

Karen Wozniak ◽

Kohtaro Fujihashi ◽

Jerry R. McGhee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Vaginal Candidiasis ◽

Wild Type ◽

Vaginal Infections ◽

Deficient Mice ◽

Δ Chain

ABSTRACT Conditions consistent with tolerance or immunoregulation have been observed in experimental Candida albicansvaginal infections. The present study investigated the role of γ/δ T cells in experimental vaginal candidiasis. Results showed that T-cell receptor δ-chain-knockout mice had significantly less vaginal fungal burden when compared to wild-type mice, suggesting an immunoregulatory role for γ/δ T cells in Candidavaginitis.

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Essential and Partially Overlapping Role of CD3γ and CD3δ for Development of αβ and γδ T Lymphocytes

Journal of Experimental Medicine ◽

10.1084/jem.188.7.1375 ◽

1998 ◽

Vol 188 (7) ◽

pp. 1375-1380 ◽

Cited By ~ 18

Author(s):

Baoping Wang ◽

Ninghai Wang ◽

Mariolina Salio ◽

Arlene Sharpe ◽

Deborah Allen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Gene Knockout ◽

Γδ T Cells ◽

Cell Receptor ◽

Γδ T Cell ◽

Thymic Development ◽

Gene Knockout Mice

CD3γ and CD3δ are two highly related components of the T cell receptor (TCR)–CD3 complex which is essential for the assembly and signal transduction of the T cell receptor on mature T cells. In gene knockout mice deficient in either CD3δ or CD3γ, early thymic development mediated by pre-TCR was either undisturbed or severely blocked, respectively, and small numbers of TCR-αβ+ T cells were detected in the periphery of both mice. γδ T cell development was either normal in CD3δ−/− mice or partially blocked in CD3γ−/− mice. To examine the collective role of CD3γ and CD3δ in the assembly and function of pre-TCR and in the development of γδ T cells, we generated a mouse strain with a disruption in both CD3γ and CD3δ genes (CD3γδ−/−). In contrast to mice deficient in either CD3γ or CD3δ chains, early thymic development mediated by pre-TCR is completely blocked, and TCR-αβ+ or TCR-γδ+ T cells were absent in the CD3γδ−/− mice. Taken together, these studies demonstrated that CD3γ and CD3δ play an essential, yet partially overlapping, role in the development of both αβ and γδ T cell lineages.

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Exacerbating Role of γδ T Cells in Chronic Colitis of T-Cell Receptor α Mutant Mice

Gastroenterology ◽

10.1053/j.gastro.2007.11.056 ◽

2008 ◽

Vol 134 (2) ◽

pp. 481-490 ◽

Cited By ~ 38

Author(s):

Masanobu Nanno ◽

Yasuyoshi Kanari ◽

Tomoaki Naito ◽

Nagamu Inoue ◽

Tadakazu Hisamatsu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Γδ T Cells ◽

Cell Receptor ◽

Mutant Mice ◽

Chronic Colitis

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The Mouse Cd1d-Restricted Repertoire Is Dominated by a Few Autoreactive T Cell Receptor Families

Journal of Experimental Medicine ◽

10.1084/jem.193.8.893 ◽

2001 ◽

Vol 193 (8) ◽

pp. 893-904 ◽

Cited By ~ 137

Author(s):

Se-Ho Park ◽

Angela Weiss ◽

Kamel Benlagha ◽

Tim Kyin ◽

Luc Teyton ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Γδ T Cells ◽

Cell Receptor ◽

Autoreactive T Cell ◽

Tcr Repertoire ◽

Nk T Cells ◽

Innate Lymphocytes ◽

Deficient Mice

To define the phenotype and T cell receptor (TCR) repertoire of CD1d-dependent T cells, we compared the populations of T cells that persisted in major histocompatibility complex (MHC)-deficient mice, which lack mainstream T cells, with those from MHC/CD1d doubly deficient mice, which lack both mainstream and CD1d-dependent T cells. Surprisingly, up to 80% of the CD1d-dependent T cells were stained by tetramers of CD1d/α-galactosylceramide, which specifically identify the previously described CD1d autoreactive Vα14-Jα18/Vβ8 natural killer (NK) T cells. Furthermore, zooming in on the CD1d-dependent non-Vα14 T cells, we found that, like Vα14 NK T cells, they mainly expressed recurrent, CD1d autoreactive TCR families and had a natural memory phenotype. Thus, CD1d-restricted T cells differ profoundly from MHC-peptide–specific T cells by their predominant use of autoreactive and semiinvariant, rather than naive and diverse, TCRs. They more closely resemble other lineages of innate lymphocytes such as B-1 B cells, γδ T cells, and NK cells, which express invariant or semiinvariant autoreactive receptors. Finally, we demonstrate that the MHC-restricted TCR repertoire is essentially non–cross-reactive to CD1d. Altogether, these findings imply that lipid recognition by CD1d-restricted T cells may have largely evolved as an innate rather than an adaptive arm of the mouse immune system.

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