Death and transfiguration of cortical thymocytes: a reconsideration

doi:10.1016/0167-5699(90)90047-D

Immunology Today

Volume 11, 1990, Pages 116-119

https://doi.org/10.1016/0167-5699(90)90047-D Get rights and content

Abstract

The fate of most cells in the mammalian thymus, namely CD4⁺CD8⁺ (double positive) cortical cells, is unknown. A fraction of the cells in this population serve as developmental intermediates, but the vast majority will die. In this article Ellen Rothenberg discusses how and when the cells are condemned or promoted to maturity, in the light of intriguing new data that suggests that they may be able to be rescued for longer than was previously thought.

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Insights into the mechanisms of thymus involution and regeneration by modeling the glucocorticoid-induced perturbation of thymocyte populations dynamics
2014, Journal of Theoretical Biology
Citation Excerpt :
The CD4+CD8+ double-positive thymocytes undergo a rapid turnover, roughly one third of them die every day but are replaced by proliferation of the remaining thymocytes (Rothenberg, 1990). These cells are the most sensitive to glucocorticoids, as a slight elevation of glucocorticoids could almost entirely wipe out the double-positive population by apoptosis and inhibition of their proliferation, with just a small population of glucocorticoid-resistant thymocytes remaining (Rothenberg, 1990; Wyllie, 1980; Chow et al., 1997). Because of this glucocorticoid sensitivity, the thymus as an organ and the thymocytes within it are very sensitive to any stressful situation, be it physiological and transient (Concordet and Ferry, 1993) or pathological and long term such as obesity, diabetes and infections (Lynch et al., 2009; Verinaud et al., 2004).
T-cells develop in the thymus and based on CD4 and CD8 expressions there are four main thymocyte populations in a normal mouse thymus. Currently, there are several mathematical models that describe the dynamics of thymocyte populations in a normal thymus, but only a few of them model the transient perturbation of their homeostasis. Our aim is to model the perturbation in the dynamics of each thymocyte population which is induced by the administration of a glucocorticoid, i.e. dexamethasone. The proposed approach relies on extending a four compartment thymus model based on differential equations by adding perturbation terms either globally (at the level of each equation) or locally (at the level of proliferation, death, and transfer rates). By fitting the perturbed model with experimental data on mice thymi collected before and after the administration of dexamethasone, it was possible to estimate the relevant parameters using a population-based stochastic search method. The fitted model is further used to conduct a quantitative analysis on the differentiated impact of dexamethasone on each T-cell population and on proliferation, death, and transfer processes. The obtained quantitative information on the perturbation could be used to explore and modify the flow of thymocytes between thymus compartments in order to elucidate the mechanisms of thymus involution and its subsequent regeneration. Since glucocorticoids are raised in many pathological situations, such a model could be useful in evaluating the impact of diseases on thymocyte dynamics in the thymus.
Prostaglandin E<inf>2</inf> and stem cell factor can deliver opposing signals to B lymphocyte precursors
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The synthetic prostanoid, 16,16-dimethyl PGE₂, suppressed B lymphopoiesis in mice and proliferation of normal B cell precursors or the F10 pro-B cell line to interleukin 7 in culture. This was not the case with two other prostanoids, PGD₂ and PGF_2α, or agonists for PGI₂ agonist and thromboxane A₂ agonist receptors. PGE₂, but not the related prostanoids or agonists, induced apoptosis in F10 cells. The apoptotic response was mediated by the EP2 class of PGE₂ receptors and required an increase in intracellular cyclic adenosine 3′,5′-monophosphate, activation of protein kinase A, and protein synthesis. The influence of PGE₂ on F10 cells was diminished in the presence of a cloned stromal cell line or stem cell factor. These findings describe another potential regulatory circuit in bone marrow which might influence B lymphopoiesis under disease or steady-state conditions.
Infectious pancreatic necrosis virus induces apoptosis due to down-regulation of survival factor MCL-1 protein expression in a fish cell line
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Infectious pancreatic necrosis virus (IPNV), a member of the virus family Birnaviridae, causes an acute, contagious disease in a number of economically important fish species. CHSE-214, a Chinook salmon embryonic cell line, when infected by IPNV showed morphological and biochemical features of apoptosis, including an intense DNA laddering pattern and blebbing of the plasma membrane, followed by formation of apoptotic bodies. The Mcl-1 gene product proved to be a member of the Bcl-2 gene family, and like Bcl-2 had the capacity to promote cell viability. Here, we investigated the pattern of expression of Mcl-1 in CHSE-214 cells infected by IPNV. We found that the Mcl-1 level decreased markedly in cells undergoing apoptosis after IPNV infection. This decrease was rapid during the first 8 h postinfection and preceded cell death. Furthermore, we found that drugs including cycloheximide, genistein and EDTA either prevented the decline in Mcl-1 levels or blocked the intense DNA laddering pattern. Other drugs like serine proteinase inhibitor, 400 μg/ml aprotinin, 400 μg/ml leupeptin and 100 μg/ml tryphostin did not. The virus gene expression pattern was examined by Western blot using antivirion polyclonal antibody and was blocked during treatment with cycloheximide, genistein and EDTA but not by serine proteinase, aprotinin, leupeptin or tryphostin. Together the data showed a striking correlation between virus replication and Mcl-1 expression in CHSE-214 cells, suggesting that the virus gene expression has a possible involvement with Mcl-1 in the regulation of apoptosis in these cells.
Gangliosides enhance apoptosis of thymocytes
1998, Cellular Immunology
Monosialogangliosides, normal components of cell membranes, regulate cell development and differentiation in several organs. Our previous observation of dramatic premature thymic involution in cats with feline GM1 gangliosidosis, whose thymocytes have abnormally high cell surface gangliosides, suggested that excess GM1 ganglioside (GM1) could modulate thymocyte apoptosis in this disease (Coxet al.,“Thymic Alterations in Feline GM1 Gangliosidosis,” submitted). In these studies, we added exogenous GM1 to murine primary thymocyte cultures and demonstrated enhanced apoptosis in treated cells by DNA fragmentation, apoptotic body, and electrophoretic analyses. GM1-enhanced apoptosis was blocked by common apoptotic pathway inhibitors including aurintricarboxylic acid (inhibitor of endonuclease activity), actinomycin D (inhibitor of RNA transcription), and cycloheximide (inhibitor of protein synthesis). GM1 treatment primarily affected the immature CD4⁺CD8⁺subset, as shown by flow cytometric evaluation of fetal thymic organ culture and primary thymocyte cultures. Apoptosis also could be induced by GM2, GM3, and GT1b, whereas asialo-GM1 failed to do so, suggesting that the sialic acid moiety may play an important role in the induction of thymocyte apoptosis.
Semi-quantitative polymerase chain reaction analysis of cytokine and cytokine receptor gene expression during thymic ontogeny
1997, Cytokine
Semi-quantitative, polymerase chain reaction (PCR) is used to uncover the patterns of cytokine transcription in the mouse thymus from day 14 to day 20 of gestation, a time period which includes many of the important events in thymic ontogeny. Interleukin 4 (IL-4), IL-7 and interferon γ (IFN-γ) mRNA is abundant from fetal day (Fd) 14–16, corresponding with the period of rapid proliferation of immature thymocytes in vivo. As the level of mRNA for these cytokines diminishes, the induction and increased expression of IL-3 and IL-2 occurs. The transcription of these cytokines correlates temporally with the period of proliferation-dependent phenotypic differentiation between Fd 16 and 20. The thymic epithelium (TE)-derived cytokines including IL-1α, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) begin to be transcribed between Fd 14–15 and show peak mRNA abundance from Fd 16-20. IL-5, tumour necrosis factor α (TNF-α) and LT (lymphotoxin or TNF-β) constitute a fourth group of cytokines, along with the IL-4 receptor (IL-4R), which are transcribed at an even level throughout the fetal period. The IL-2 receptor beta chain (IL-2Rβ) and IL-10 show abundant mRNA from Fd 14–20 and have a peak level of mRNA content on Fd 16. Taken together, these studies uncover complex, overlapping patterns of cytokine gene expression. The mRNA abundance and pattern of expression of each cytokine or cytokine receptor may indicate the relative contribution that it makes to different stages of fetal thymic ontogeny.
Dose-dependent opposite effect of zinc on apoptosis in mouse thymocytes
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Zinc is a crucial nutritional component required for the normal development and maintenance of immune functions. It has been reported that zinc is a potent inhibitor of DNA fragmentation, the specific marker of apoptosis. The effect of zinc on apoptotic cell death has been previously studied in a narrow range of high zinc concentrations, and the role of physiological zinc doses has not yet been elucidated. In this paper we evaluate the effect of in vitro Zn²⁺ administration at concentrations higher than, corresponding to, and lower than the physiological concentration, in thymocytes from young mice. We demonstrate that Zn²⁺ has an opposite effect on apoptosis, inhibiting or increasing it depending on the Zn²⁺ concentration used. High Zn²⁺ concentrations (from 600 to 75 μM) inhibit both serum-free medium and DEX-induced thymocyte apoptosis. Low Zn²⁺ concentrations (from 15 to 7.5 μM) induce apoptosis or increase serum-free medium-induced apoptosis. The effect of low Zn²⁺ concentrations on DEX-induced apoptosis is dependent on the length of incubation, since Zn²⁺ has an additive effect with DEX in inducing DNA fragmentation at 8 h of culture, whereas it blocks DEX-induced apoptosis after 20 h incubation. Both DEX and 15 μM Zn²⁺-induced DNA fragmentation require protein synthesis, being blocked through cycloheximide. The inhibiting and inducing effects of Zn²⁺ on apoptosis are exerted on G₀/G₁ phase thymocytes. The inhibiting effect of Zn²⁺ on apoptosis is related to an increase in the number of CD4⁺CD8⁺ thymocytes. Concentrations of Zn²⁺ inducing apoptosis sometimes cause a decrease of CD4⁺CD8⁻ cells with a corresponding increase of CD4⁺CD8⁻thymocytes. These data show that in vitro Zn²⁺ has a dose-dependent opposite effect on apoptosis, suggesting that Zn²⁺ not only acts as an inhibitor but also plays a more complex role in physiological intrathymic cell selection.

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RostrumDeath and transfiguration of cortical thymocytes: a reconsideration

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Death and transfiguration of cortical thymocytes: a reconsideration