scholarly journals Interleukin-4 protects double-negative and CD4 single-positive thymocytes from dexamethasone-induced apoptosis

Blood ◽  
1993 ◽  
Vol 81 (5) ◽  
pp. 1352-1358 ◽  
Author(s):  
G Migliorati ◽  
I Nicoletti ◽  
MC Pagliacci ◽  
L D'Adamio ◽  
C Riccardi
Keyword(s):  
T Cell ◽  
Time Course ◽  
T Cell Development ◽  
Cell Tumor ◽  
Interleukin 4 ◽  
Double Negative ◽  
Phenotypic Analysis ◽  
Cd8 Cells ◽  
Single Positive ◽  
Induced Apoptosis

Abstract Glucocorticoid hormones (GCH) and anti-CD3 monoclonal antibodies (MoAbs) induce in mouse thymocytes and T-cell tumor lines an active process of cell death called apoptosis. Interleukins (IL), including IL- 1 and IL-2, have been reported to inhibit such apoptosis. In this study we show that IL-4 also reduced the DNA fragmentation characteristic of dexamethasone (DEX)-induced apoptosis in thymocytes. This effect, studied in both time-course and dose-response experiments, was also detected at low IL-4 concentrations (1 U/mL) and against high DEX levels (10(-7) mol/L). The effect of IL-4 was blocked by an anti-IL-4 but not by an anti-IL-1 alpha MoAb, and was thus both specific and direct. Phenotypic analysis showed that IL-4 protects predominantly CD4- CD8- and CD4+CD8- cells. Our findings suggest that intrathymic T-cell development may be influenced by IL-4.

scholarly journals Interleukin-4 protects double-negative and CD4 single-positive thymocytes from dexamethasone-induced apoptosis

Blood ◽  
1993 ◽  
Vol 81 (5) ◽  
pp. 1352-1358 ◽  
Author(s):  
G Migliorati ◽  
I Nicoletti ◽  
MC Pagliacci ◽  
L D'Adamio ◽  
C Riccardi
Keyword(s):  
T Cell ◽  
Time Course ◽  
T Cell Development ◽  
Cell Tumor ◽  
Interleukin 4 ◽  
Double Negative ◽  
Phenotypic Analysis ◽  
Cd8 Cells ◽  
Single Positive ◽  
Induced Apoptosis

Glucocorticoid hormones (GCH) and anti-CD3 monoclonal antibodies (MoAbs) induce in mouse thymocytes and T-cell tumor lines an active process of cell death called apoptosis. Interleukins (IL), including IL- 1 and IL-2, have been reported to inhibit such apoptosis. In this study we show that IL-4 also reduced the DNA fragmentation characteristic of dexamethasone (DEX)-induced apoptosis in thymocytes. This effect, studied in both time-course and dose-response experiments, was also detected at low IL-4 concentrations (1 U/mL) and against high DEX levels (10(-7) mol/L). The effect of IL-4 was blocked by an anti-IL-4 but not by an anti-IL-1 alpha MoAb, and was thus both specific and direct. Phenotypic analysis showed that IL-4 protects predominantly CD4- CD8- and CD4+CD8- cells. Our findings suggest that intrathymic T-cell development may be influenced by IL-4.

scholarly journals A Role for Bcl-2 in Notch1-Dependent Transcription in Thymic Lymphoma Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Ronit Vogt Sionov ◽  
Shlomit Kfir-Erenfeld ◽  
Rachel Spokoini ◽  
Eitan Yefenof
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Double Negative ◽  
Double Positive ◽  
Lymphoma Cells ◽  
Thymic Lymphoma ◽  
Induced Apoptosis

Notch1 is a transcription factor important for T-cell development. Notch1 is active in double negative (DN) thymocytes, while being depressed in double positive (DP) thymocytes. Synchronously, the expression of Bcl-2 becomes downregulated during the transition from DN to DP thymocytes. We previously observed that overexpression of an intracellular active Notch1 (ICN) in Bcl-2-positive 2B4 T cells leads to the transcription of Notch1-regulated genes. However, these genes were not induced in Bcl-2-negative DP PD1.6 thymic lymphoma cells overexpressing ICN. Here we show that, when Bcl-2 is simultaneously introduced into these cells, Notch-regulated genes are transcribed. Only in the presence of both Bcl-2 and ICN, PD1.6 thymic lymphoma cells become resistant to glucocorticoid (GC)-induced apoptosis. Our data suggest that Bcl-2 plays a role in modulating Notch1 function in T cells.

scholarly journals Defective development of thymocytes overexpressing the costimulatory molecule, heat-stable antigen.

1994 ◽  
Vol 179 (1) ◽  
pp. 177-184 ◽  
Author(s):  
M R Hough ◽  
F Takei ◽  
R K Humphries ◽  
R Kay
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Costimulatory Molecule ◽  
Cell Development ◽  
Double Negative ◽  
Double Positive ◽  
Heat Stable ◽  
Heat Stable Antigen ◽  
Single Positive

Heat-stable antigen (HSA) is a small, glycosyl phosphatidylinositol-anchored protein that can act as a costimulatory molecule for antigen-dependent activation of helper T cells. In addition to being expressed on antigen-presenting B cells, HSA is also expressed during the initial stages of T cell development in the thymus. HSA levels are very high on immature CD4-, CD8- double negative thymocytes, but are reduced on CD4+, CD8+ double positive cells undergoing selection in the thymus, and are entirely eliminated when these cells differentiate into immunologically competent CD4+ or CD8+ single positive T cells. To examine the potential roles of this molecule in T cell development and selection, we generated transgenic mice in which HSA was highly expressed on all classes of thymocytes. The consequence of deregulated HSA expression was a pronounced reduction in the numbers of double positive and single positive thymocytes, whereas the numbers of their double negative precursors were largely unaffected. These results demonstrate that downregulation of HSA expression at the double positive stage is a critical event in thymocyte development. The depletion of thymocytes resulting from HSA overexpression begins at the same time as the onset of negative selection, suggesting that HSA may provide signals that contribute to determining the efficiency of this process.

scholarly journals Histone Deacetylase 3 Is Required for Efficient T Cell Development

2015 ◽  
Vol 35 (22) ◽  
pp. 3854-3865 ◽  
Author(s):  
Kristy R. Stengel ◽  
Yue Zhao ◽  
Nicholas J. Klus ◽  
Jonathan F. Kaiser ◽  
Laura E. Gordy ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Hdac Inhibitors ◽  
Cell Receptor ◽  
Cell Development ◽  
Open Chromatin ◽  
Double Negative ◽  
Thymocyte Development ◽  
Double Positive ◽  
Single Positive

Hdac3 is a key target for Hdac inhibitors that are efficacious in cutaneous T cell lymphoma. Moreover, the regulation of chromatin structure is critical as thymocytes transition from an immature cell with open chromatin to a mature T cell with tightly condensed chromatin. To define the phenotypes controlled by Hdac3 during T cell development, we conditionally deletedHdac3using theLck-Cretransgene. This strategy inactivatedHdac3in the double-negative stages of thymocyte development and caused a significant impairment at the CD8 immature single-positive (ISP) stage and the CD4/CD8 double-positive stage, with few mature CD4+or CD8+single-positive cells being produced. WhenHdac3−/−mice were crossed withBcl-xL-,Bcl2-, orTCRβ-expressing transgenic mice, a modest level of complementation was found. However, when the null mice were crossed with mice expressing a fully rearranged T cell receptor αβ transgene, normal levels of CD4 single-positive cells were produced. Thus, Hdac3 is required for the efficient transit from double-negative stage 4 through positive selection.

Altered thymocyte and T cell development in neonatal mice with hyperoxia-induced lung injury

2018 ◽  
Vol 46 (4) ◽  
pp. 441-449
Author(s):  
Sowmya Angusamy ◽  
Tamer Mansour ◽  
Mohammed Abdulmageed ◽  
Rachel Han ◽  
Brian C. Schutte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Injury ◽  
T Cell Development ◽  
Adaptive Immune System ◽  
Cell Development ◽  
Thymocyte Development ◽  
Double Positive ◽  
Neonatal Mice ◽  
Single Positive

Abstract Background: The adaptive immune system of neonates is relatively underdeveloped. The thymus is an essential organ for adaptive T cell development and might be affected during the natural course of oxygen induced lung injury. The effect of prolonged hyperoxia on the thymus, thymocyte and T cell development, and its proliferation has not been studied extensively. Methods: Neonatal mice were exposed to 85% oxygen (hyperoxia) or room air (normoxia) up to 28 days. Flow cytometry using surface markers were used to assay for thymocyte development and proliferation. Results: Mice exposed to prolonged hyperoxia had evidence of lung injury associated alveolar simplification, a significantly lower mean weight, smaller thymic size, lower mean thymocyte count and higher percentage of apoptotic thymocytes. T cells subpopulation in the thymus showed a significant reduction in the count and proliferation of double positive and double negative T cells. There was a significant reduction in the count and proliferation of single positive CD4+ and CD8+ T cells. Conclusions: Prolonged hyperoxia in neonatal mice adversely affected thymic size, thymocyte count and altered the distribution of T cells sub-populations. These results are consistent with the hypothesis that prolonged hyperoxia causes defective development of T cells in the thymus.

scholarly journals The effect of in vivo IL-7 deprivation on T cell maturation.

1995 ◽  
Vol 181 (4) ◽  
pp. 1399-1409 ◽  
Author(s):  
S K Bhatia ◽  
L T Tygrett ◽  
K H Grabstein ◽  
T J Waldschmidt
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Present Report ◽  
Critical Role ◽  
Cell Maturation ◽  
Double Negative ◽  
Heat Stable Antigen ◽  
Single Positive

A number of previous studies have suggested a key role for interleukin 7 (IL-7) in the maturation of T lymphocytes. To better assess the function of IL-7 in lymphopoiesis, we have deprived mice of IL-7 in vivo by long-term administration of a neutralizing anti-IL-7 antibody. In a previous report (Grabstein, K. H., T. J. Waldschmidt, F. D. Finkelman, B. W. Hess, A. R. Alpert, N. E. Boiani, A. E. Namen, and P. J. Morrissey. 1993. J. Exp. Med. 178:257-264), we used this system to demonstrate the critical role of IL-7 in B cell maturation. After a brief period of anti-IL-7 treatment, most of the pro-B cells and all of the pre-B and immature B cells were depleted from the bone marrow. In the present report, we have injected anti-IL-7 antibody for periods of up to 12 wk to determine the effect of in vivo IL-7 deprivation on the thymus. The results demonstrate a > 99% reduction in thymic cellularity after extended periods of antibody administration. Examination of thymic CD4- and CD8- defined subsets revealed that, on a proportional basis, the CD4+, CD8+ subset was most depleted, the CD4 and CD8 single positive cells remained essentially unchanged, and the CD4-, CD8- compartment actually increased to approximately 50% of the thymus. Further examination of the double negative thymocytes demonstrated that IL-7 deprivation did, indeed, deplete the CD3-, CD4-, CD8- precursors, with expansion of this subset being interupted at the CD44+, CD25+ stage. The proportional increase in the CD4-, CD8- compartment was found to be due to an accumulation of CD3+, T cell receptor alpha, beta + double negative T cells. Additional analysis revealed that anti-IL-7 treatment suppressed the audition/selection process of T cells, as shown by a significant reduction of single positive cells expressing CD69 and heat stable antigen. Finally, the effects of IL-7 deprivation on the thymus were found to be reversible, with a normal pattern of thymic subsets returning 4 wk after cessation of treatment. The present results thus indicate a central role for IL-7 in the maturation of thymic-derived T cells.

scholarly journals Enforced Expression of GATA-3 During T Cell Development Inhibits Maturation of CD8 Single-Positive Cells and Induces Thymic Lymphoma in Transgenic Mice

2001 ◽  
Vol 167 (2) ◽  
pp. 715-723 ◽  
Author(s):  
Martijn C. Nawijn ◽  
Rita Ferreira ◽  
Gemma M. Dingjan ◽  
Olev Kahre ◽  
Dubravka Drabek ◽  
...  
Keyword(s):  
T Cell ◽  
Transgenic Mice ◽  
T Cell Development ◽  
Cell Development ◽  
Thymic Lymphoma ◽  
Single Positive

scholarly journals The transcriptional regulator PLZF induces the development of CD44 high memory phenotype T cells

2008 ◽  
Vol 105 (46) ◽  
pp. 17919-17924 ◽  
Author(s):  
Julia Raberger ◽  
Alexandra Schebesta ◽  
Shinya Sakaguchi ◽  
Nicole Boucheron ◽  
K. Emelie M. Blomberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Development ◽  
Transgenic Expression ◽  
Memory Phenotype ◽  
Single Positive ◽  
Broad Complex ◽  
Killer T Cells ◽  
Subset Distribution ◽  
Intrinsic Program

Transcriptional pathways controlling the development of CD44hi memory phenotype (MP) T cells with “innate-like” functions are not well understood. Here we show that the BTB (bric-a-brac, tramtrack, broad complex) domain-containing protein promyelocytic leukemia zinc finger (PLZF) is expressed in CD44hi, but not in CD44lo, CD4+ T cells. Transgenic expression of PLZF during T cell development and in CD4+ and CD8+ T cells induced a T cell intrinsic program leading to an increase in peripheral CD44hi MP CD4+ and CD8+ T cells and a corresponding decrease of naïve CD44lo T cells. The MP CD4+ and CD8+ T cells produced IFNγ upon PMA/ionomycin stimulation, thus showing innate-like function. Changes in the naïve versus memory-like subset distribution were already evident in single-positive thymocytes, indicating PLZF-induced T cell developmental alterations. In addition, CD1d-restricted natural killer T cells in PLZF transgenic mice showed impaired development and were severely reduced in the periphery. Finally, after anti-CD3/CD28 stimulation, CD4+ transgenic T cells showed reduced IL-2 and IFNγ production but increased IL-4 secretion as a result of enhanced IL-4 production of the CD44hiCD62L+ subset. Our data indicate that PLZF is a novel regulator of the development of CD44hi MP T cells with a characteristic partial innate-like phenotype.

Functional double-negative T cells in the periphery express T cell receptor Vβ gene products that cause deletion of single-positive T cells

1993 ◽  
Vol 23 (1) ◽  
pp. 250-254 ◽  
Author(s):  
Carlos Martínez-a ◽  
Miguel A. R. Marcos ◽  
Ignacio M. de Alboran ◽  
José María Alonso ◽  
Rafael de Cid ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Double Negative ◽  
Gene Products ◽  
Single Positive ◽  
Double Negative T Cells ◽  
T Cell Receptor Vβ

scholarly journals Defined αβ T Cell Receptors with Distinct Ligand Specificities Do Not Require Those Ligands to Signal Double Negative Thymocyte Differentiation

2004 ◽  
Vol 199 (12) ◽  
pp. 1719-1724 ◽  
Author(s):  
Batu Erman ◽  
Terry I. Guinter ◽  
Alfred Singer
Keyword(s):  
T Cell ◽  
T Cell Development ◽  
Cell Receptor ◽  
Peptide Ligands ◽  
Double Negative ◽  
Antigen Receptors ◽  
Double Positive ◽  
Recombination Activating Gene ◽  
Thymocyte Differentiation ◽  
Deficient Mice

During T cell development in the thymus, pre–T cell receptor (TCR) complexes signal CD4− CD8− (double negative [DN]) thymocytes to differentiate into CD4+ CD8+ (double positive [DP]) thymocytes, and they generate such signals without apparent ligand engagements. Although ligand-independent signaling is unusual and might be unique to the pre-TCR, it is possible that other TCR complexes such as αβ TCR or αγ TCR might also be able to signal the DN to DP transition in the absence of ligand engagement if they were expressed on DN thymocytes. Although αγ TCR complexes efficiently signal DN thymocyte differentiation, it is not yet certain if αβ TCR complexes are also capable of signaling DN thymocyte differentiation, nor is it certain if such signaling is dependent upon ligand engagement. This study has addressed these questions by expressing defined αβ TCR transgenes in recombination activating gene 2−/− pre-Tα−/− double deficient mice. In such double deficient mice, the only antigen receptors that can be expressed are those encoded by the αβ TCR transgenes. In this way, this study definitively demonstrates that αβ TCR can in fact signal the DN to DP transition. In addition, this study demonstrates that transgenic αβ TCRs signal the DN to DP transition even in the absence of their specific MHC–peptide ligands.

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