Evidence That γδ versus αβ T Cell Fate Determination Is Initiated Independently of T Cell Receptor Signaling

Two types of T cells, αβ and γδ, develop in vertebrates. How these two T cell lineages arise from a common thymic T progenitor is poorly understood. Differentiation of αβ lineage T cells requires the surrogate α chain (pTα), which associates with the T cell receptor (TCR) β chain to form the pre-TCR. γδ lineage development does not appear to involve an obligatory surrogate chain, but instead requires productive rearrangement and expression of both TCR γ and δ genes. It has been proposed that the quality of signals transmitted by the pre-TCR and γδ TCR are distinct and that these “instructive” signals determine the lineage fate of an uncommitted progenitor cell. Here we show that the thymic T progenitor cells (CD25+CD44+c-kit+CD3−CD4−CD8− thymocytes, termed pro-T cells) from young adult mice that have yet to express TCRs can be subdivided based on interleukin 7 receptor (IL-7R) expression. These subsets exhibit differential potential to develop into γδ versus αβ lineage (CD4+CD8+ cells) in the thymus. Upon intrathymic injection, IL-7Rneg-lo pro-T cells generated a 13-fold higher ratio of αβ lineage to γδ lineage cells than did IL-7R+ pro-T cells. Much of this difference was due to a fivefold greater potential of IL-7R+ pro-T cells to develop into TCR-γδ T cells. Evidence indicates that this biased developmental potential is not a result of enhanced TCR-γ gene rearrangement/expression in IL-7R+ pro-T cells. These results indicate that the pro-T cells are heterogeneous in developmental potential before TCR gene rearrangement and suggest that in some precursor cells the initial lineage commitment is independent of TCR-mediated signals.

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Premature Expression of T Cell Receptor (Tcr)αβ Suppresses Tcrγδ Gene Rearrangement but Permits Development of γδ Lineage T Cells

Journal of Experimental Medicine ◽

10.1084/jem.192.4.537 ◽

2000 ◽

Vol 192 (4) ◽

pp. 537-548 ◽

Cited By ~ 98

Author(s):

Kathleen Terrence ◽

Christian P. Pavlovich ◽

Errin O. Matechak ◽

B.J. Fowlkes

Keyword(s):

T Cells ◽

T Cell ◽

Transgenic Mice ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Gene Rearrangement ◽

T Cell Development ◽

Cell Receptor ◽

Lineage Commitment ◽

Cd8 Cells

The T cell receptor (TCR)γδ and the pre-TCR promote survival and maturation of early thymocyte precursors. Whether these receptors also influence γδ versus αβ lineage determination is less clear. We show here that TCRγδ gene rearrangements are suppressed in TCRαβ transgenic mice when the TCRαβ is expressed early in T cell development. This situation offers the opportunity to examine the outcome of γδ versus αβ T lineage commitment when only the TCRαβ is expressed. We find that precursor thymocytes expressing TCRαβ not only mature in the αβ pathway as expected, but also as CD4−CD8− T cells with properties of γδ lineage cells. In TCRαβ transgenic mice, in which the transgenic receptor is expressed relatively late, TCRγδ rearrangements occur normally such that TCRαβ+CD4−CD8− cells co-express TCRγδ. The results support the notion that TCRαβ can substitute for TCRγδ to permit a γδ lineage choice and maturation in the γδ lineage. The findings could fit a model in which lineage commitment is determined before or independent of TCR gene rearrangement. However, these results could be compatible with a model in which distinct signals bias lineage choice and these signaling differences are not absolute or intrinsic to the specific TCR structure.

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An obligate role for T-cell receptor αβ+ T cells but not T-cell receptor γδ+ T cells, B cells, or CD40/CD40L interactions in a mouse model of atopic dermatitis

Journal of Allergy and Clinical Immunology ◽

10.1067/mai.2001.112695 ◽

2001 ◽

Vol 107 (2) ◽

pp. 359-366 ◽

Cited By ~ 49

Author(s):

Amy L. Woodward ◽

Jonathan M. Spergel ◽

Harri Alenius ◽

Emiko Mizoguchi ◽

Atul K. Bhan ◽

...

Keyword(s):

T Cells ◽

Atopic Dermatitis ◽

T Cell ◽

B Cells ◽

Mouse Model ◽

T Cell Receptor ◽

Γδ T Cells ◽

Cell Receptor ◽

Αβ T Cells

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T-cell receptor gene transfer exclusively to human CD8+ cells enhances tumor cell killing

Blood ◽

10.1182/blood-2012-02-412973 ◽

2012 ◽

Vol 120 (22) ◽

pp. 4334-4342 ◽

Cited By ~ 31

Author(s):

Qi Zhou ◽

Irene C. Schneider ◽

Inan Edes ◽

Annemarie Honegger ◽

Patricia Bach ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Gene Transfer ◽

Tumor Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Cell Killing ◽

Specific Gene ◽

Cd8 Cells ◽

Tumor Cell Killing

AbstractTransfer of tumor-specific T-cell receptor (TCR) genes into patient T cells is a promising strategy in cancer immunotherapy. We describe here a novel vector (CD8-LV) derived from lentivirus, which delivers genes exclusively and specifically to CD8+ cells. CD8-LV mediated stable in vitro and in vivo reporter gene transfer as well as efficient transfer of genes encoding TCRs recognizing the melanoma antigen tyrosinase. Strikingly, T cells genetically modified with CD8-LV killed melanoma cells reproducibly more efficiently than CD8+ cells transduced with a conventional lentiviral vector. Neither TCR expression levels, nor the rate of activation-induced death of transduced cells differed between both vector types. Instead, CD8-LV transduced cells showed increased granzyme B and perforin levels as well as an up-regulation of CD8 surface expression in a small subpopulation of cells. Thus, a possible mechanism for CD8-LV enhanced tumor cell killing may be based on activation of the effector functions of CD8+ T cells by the vector particle displaying OKT8-derived CD8-scFv and an increase of the surface density of CD8, which functions as coreceptor for tumor-cell recognition. CD8-LV represents a powerful novel vector for TCR gene therapy and other applications in immunotherapy and basic research requiring CD8+ cell-specific gene delivery.

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Localization of T cell receptor (TCR)- γδ+ T cells into human colorectal cancer: flow cytometric analysis of TCR-γδ expression in tumour-infiltrating lymphocytes

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.1995.tb06651.x ◽

2008 ◽

Vol 102 (1) ◽

pp. 167-173 ◽

Cited By ~ 17

Author(s):

N. WATANABE ◽

A. HIZUTA ◽

N. TANAKA ◽

K. ORITA

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Flow Cytometric Analysis ◽

Γδ T Cells ◽

Cell Receptor ◽

Human Colorectal Cancer ◽

Flow Cytometric ◽

Infiltrating Lymphocytes

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Differential Susceptibility of Naïve and Activated Human γδ T Cells to Activation-Induced Cell Death by T-Cell Receptor Cross-Linking

Molecular Medicine ◽

10.1007/bf03401870 ◽

2001 ◽

Vol 7 (9) ◽

pp. 636-643 ◽

Cited By ~ 9

Author(s):

Yunn-Hwen Gan ◽

Shirley S. N. Lui ◽

Miroslav Malkovsky

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

T Cell Receptor ◽

Differential Susceptibility ◽

Γδ T Cells ◽

Cell Receptor ◽

Cross Linking ◽

Activation Induced Cell Death

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

Journal of Experimental Medicine ◽

10.1084/jem.194.10.1473 ◽

2001 ◽

Vol 194 (10) ◽

pp. 1473-1483 ◽

Cited By ~ 39

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.

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Interleukin-7 Enhances Proliferation Responses to T-Cell Receptor Stimulation in Naïve CD4+ T Cells from Human Immunodeficiency Virus-Infected Persons

Journal of Virology ◽

10.1128/jvi.00476-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12670-12674 ◽

Cited By ~ 14

Author(s):

Douglas A. Bazdar ◽

Scott F. Sieg

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Healthy Controls ◽

Receptor Stimulation ◽

Interleukin 7 ◽

Immunodeficiency Virus ◽

Antigen Presenting

ABSTRACT Proliferation responses of naïve CD4+ T cells to T-cell receptor and interleukin-7 (IL-7) stimulation were evaluated by using cells from human immunodeficiency virus-positive (HIV+) donors. IL-7 enhanced responses to T-cell receptor stimulation, and the magnitude of this enhancement was similar in cells from healthy controls and from HIV+ subjects. The overall response to T-cell receptor stimulation alone or in combination with IL-7, however, was diminished among viremic HIV+ donors and occurred independent of antigen-presenting cells. Frequencies of CD127+ cells were related to the magnitudes of proliferation enhancement that were mediated by IL-7. Thus, IL-7 enhances but does not fully restore the function of naïve CD4+ T cells from HIV-infected persons.

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Interleukin 7 Receptor Control of T Cell Receptor γ Gene Rearrangement: Role of Receptor-associated Chains and Locus Accessibility

Journal of Experimental Medicine ◽

10.1084/jem.188.12.2233 ◽

1998 ◽

Vol 188 (12) ◽

pp. 2233-2241 ◽

Cited By ~ 93

Author(s):

Scott K. Durum ◽

Serge Candèias ◽

Hiroshi Nakajima ◽

Warren J. Leonard ◽

Allison M. Baird ◽

...

Keyword(s):

Transcription Factors ◽

T Cell ◽

T Cell Receptor ◽

Dna Cleavage ◽

Gene Rearrangement ◽

Trichostatin A ◽

Cell Receptor ◽

Lymphoid Cells ◽

Janus Kinase ◽

Interleukin 7

VDJ recombination of T cell receptor and immunoglobulin loci occurs in immature lymphoid cells. Although the molecular mechanisms of DNA cleavage and ligation have become more clear, it is not understood what controls which target loci undergo rearrangement. In interleukin 7 receptor (IL-7R)α−/− murine thymocytes, it has been shown that rearrangement of the T cell receptor (TCR)-γ locus is virtually abrogated, whereas other rearranging loci are less severely affected. By examining different strains of mice with targeted mutations, we now observe that the signaling pathway leading from IL-7Rα to rearrangement of the TCR-γ locus requires the γc receptor chain and the γc-associated Janus kinase Jak3. Production of sterile transcripts from the TCR-γ locus, a process that generally precedes rearrangement of a locus, was greatly repressed in IL-7Rα−/− thymocytes. The repressed transcription was not due to a lack in transcription factors since the three transcription factors known to regulate this locus were readily detected in IL-7Rα−/− thymocytes. Instead, the TCR-γ locus was shown to be methylated in IL-7Rα−/− thymocytes. Treatment of IL-7Rα−/− precursor T cells with the specific histone deacetylase inhibitor trichostatin A released the block of TCR-γ gene rearrangement. This data supports the model that IL-7R promotes TCR-γ gene rearrangement by regulating accessibility of the locus via demethylation and histone acetylation of the locus.

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