Characterization of thymocyte phenotypic alterations induced by long-lasting β-adrenoceptor blockade in vivo and its effects on thymocyte proliferation and apoptosis (original) (raw)
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International Immunopharmacology, 2007
Age-related increase in the density of thymic noradrenergic fibres and noradrenaline (NA) concentration is proposed to be associated with thymic involution and altered thymopoiesis. To test this hypothesis thymocyte differentiation/maturation and thymic structure were studied in 18-month-old male Wistar rats subjected to 14-day-long propranolol (P) blockade of β-adrenoceptors (β-ARs). The treatment primarily resulted in changes in the T-cell receptor (TCR)-dependent stages of thymopoiesis, which led to an increase in both the relative and absolute numbers of the most mature single positive (SP) CD4 + CD8 − (including cells with the CD4 + CD25 + regulatory phenotype) and CD4 − CD8 + TCRαβ high thymocytes. Accordingly, in the thymi of these rats an increase in both numerical density and absolute number of medullary thymocytes encompassing mainly the most mature SP cells was found. These findings, together with an increase in the thymocyte surface expression of the regulatory molecule Thy-1 (CD90) (implicated in negative regulation of TCRαβ-dependent thymocyte selection thresholds) in the same rats, may suggest increased positive/reduced negative thymocyte selection. Collectively, the results indicate that a decline in thymic efficiency in generating both conventional and regulatory T cells, and consequently in immune function, in aged rats may be, at least partly, attenuated by long-term blockade of β-ARs with P.
Autonomic Neuroscience, 2008
In its simplest form, effective T cell-mediated immunity emanates from the expansion of specific T cells activated in response to antigen. In establishing and maintaining the peripheral T-cell pool, the thymus plays a critical role. It does so by providing a microenvironment within which T-cell precursors proliferate, differentiate and undergo selection processes to create a fully functional population of major histocompatibility complex restricted, selftolerant T cells. The control of the thymic function involves intrathymic, as well as sympathetic nervous and endocrine system signalling. In addition to postganglionic noradrenergic fibres, both thymic lymphoid and nonlymphoid cells, including epithelial cells and macrophages, have been demonstrated to express tyrosine hydroxylase (TH), and suggested to form a local non-neural catecholaminergic cell network. A higher level of noradrenaline has been found in male than in female rat thymi, and a role of gonadal hormones in providing this dimorphism has been demonstrated. In addition, thymic lymphoid and non-lymphoid cells, including those expressing TH, have been found to bear βand α 1 -adrenoceptors (ARs) and a role of gonadal hormones in regulation of, at least, β-AR density and signalling has been suggested. These findings have also entailed conclusion that catecholamines (CAs) influence T-cell development, not only via neurocrine/endocrine, but also via autocrine/paracrine action. Generally, CAs have been shown to exert an inhibitory influence on thymopoiesis. Role of α 1 -and β-AR-mediated mechanisms in maintaining thymic homeostasis and in fine tuning of both conventional and regulatory T-cell development is discussed in the manuscript.
Age-associated plasticity of α1-adrenoceptor-mediated tuning of T-cell development
Experimental Gerontology, 2010
Alpha 1 -adrenoceptors (α 1 -ARs) are involved in neuro-thymic and thymic intercellular communications, and consequently modulation of T-cell development. Ageing is associated with a number of changes in noradrenergic neuro-effector transmission, and possibly intercellular noradrenaline (NA)-mediated communication resulting in altered responses of target cells to NA. Thus, in old animals an altered NA modulation of thymopoiesis via α 1 -ARs may be expected. To test this hypothesis, in old and young adult Wistar rats we examined: 1) thymic NA levels, density of noradrenergic innervation and NA synthesizing cells, as well as α 1 -AR expression, and 2) then the effects of 14-day-long treatment with the α 1 -AR blocker, urapidil, on thymocyte development. Overall, the first part of study suggested augmented NA signalling to thymic cells via α 1 -ARs due to increased NA availability and α 1 -AR thymocyte surface density in old rats. The second part of study supported this assumption. Namely, although in rats of both ages urapidil affected the same thymocyte developmental steps ultimately leading to changes in the relative number of the most mature single positive TCRαβ high thymocytes, its effects were generally more prominent in old animals. Following urapidil treatment, the percentages of CD4 + CD8− cells, including those showing a regulatory CD4 + CD25 + RT6.1− phenotype, were increased, while CD4 − CD8+ cells decreased. In old rats, an augmented thymic escape of immature CD4 + CD8+ cells was also registered. In rats of both ages the thymic changes were accompanied by alterations in the proportions of major cell populations in the T-lymphocyte compartment of both peripheral blood and spleen, leading to an increase in the CD4+/CD8+ T-cell ratio. These alterations were also more pronounced in old rats. Moreover, in old rats following urapidil treatment the proportion of TCRαβ + cells in the periphery was slightly greater reflecting, most likely, partly enhanced thymic production of regulatory CD161 + TCRαβ + cells. Thus, the study indirectly suggests an ageassociated increase in the basal α 1 -AR-mediated inhibitory influence of NA on thymopoiesis.
International Journal of Immunopharmacology, 1983
Thymic hormonal effect on lymphocytotoxicity induced in vitro and its target specificity were tested using peripheral blood mononuclear cells (PBMC) of healthy subjects. PBMC were treated by the thymic extract TP-1, a similarly prepared spleen extract (SE) or medium only (1 h, 37°C) and then induced to express cytotoxic activity by exposure to allogeneic tumor cells in mixed cultures or by Con A stimulation. The cytotoxicity developed after several days in culture was assayed on ~'Cr labelled tumor cells. TP-I caused a significant mean enhancement of cytotoxicity induced and assayed on Raji lymphoma cells (mean % specific lysis, 31.5_+2.9 without TP-I and 53.7_+3.6 with TP-I; n = 42; p < 0.01). The scatter of individual responses to TP-1 was wide, however, and included also some cases of TP-1 induced suppression. Similar wide scatter of TP-I effects with emphasis on TP-1 induced enhancement was observed with other tumor cell lines or with Con A as inducers. Usually, SE had no effect on induced cytotoxicity. Target selectivity (specificity) of induced cytotoxicity was tested by induction and assay on several tumor cell lines with crossing over, as well as by cold competition assay. When target selectivity was present, it was not masked by TP-1 induced enhancement. Moreover, in some cases, target selectivity became more pronounced after TP-1 treatment, However, TP-1 enhanced also Con A induced non-specific cytotoxicity. No effect of TP-1 on natural killer cell activity of fresh PBMC could be demonstrated. It is suggested that both selective cytotoxicity (T-cell dependent) and non-selective one maybe modulated directly by TP-1 and indirectly by TP-1 modified secondary interactions in culture. This profound regulatory effects could be demonstrated in the PBMC of immuneintact healthy adults.
European Journal of Immunology, 1993
Negative selection in thymus occurs by apoptosis in CD4+CD8+ cells. These immature thymocytes are readily killed, both in v i m and in vivo, by glucocorticoid treatment. Increased levels of intracellular CAMP in vitro also induce apoptosis of thymocytes and T cell receptor (TcR) stimulation potentiate cAMP responses through receptors linked to adenylic cyclase. Presently, we have tested the possibility that TcR-mediated apoptosis in vivo may require the glucocorticoid receptor (GR) as a downstream, intracellular mediator. Use of the GR antagonist RU-486, 24 h before and simultaneous with, anti-CD3 or 5'-(N-ethyl)-carboxamide-adenosine (NECA) treatment, resulted in a selective inhibition of CD4+CD8+ thymocyte death. In addition, a low dose of glucocorticoid potentiated thymocyte death induced by anti-CD3 monoclonal antibodies. These data support a model in which thymic negative selection depends on a defined set of transduction signals which potentiate the GR to become responsive to endogenous levels of glucocorticoid.
Polish journal of pharmacology
The effect of physiological and pharmacologically induced thymus involution was studied in 12-week-old female C57BL mice. Thymus involution was estimated by measurement of the thymus weight and the ability of thymocytes to induce a graft-versus-host (GvH) reaction at 48 h after delivery or drug administration in comparison with control (virgin, saline-treated) mice. The thymus weight and immunoreactivity of thymocytes after delivery were reduced in a statistically significant manner by ca. 80 and 75%, respectively. On the other hand, hydrocortisone administration decreased the thymus weight (by ca. 60%), but did not change the ability of thymocytes to induce a GvH reaction. Cyclophosphamide administration significantly reduced both the thymus weight and the reactivity of thymocytes. The present study suggests that the transient thymus involution observed after delivery, connected with a loss of the ability of thymocytes to induce a GvH reaction, cannot be explained merely by elimina...
Thymocyte Activation and Death: a Mechanism for Molding the T Cell Repertoire
Annals of the New York Academy of Sciences, 1991
tor for antigen (TCR), either in uiuo or in fetal tissue organ culture, leads to PCD.4.11,'8 This last experimental model is thought to reflect the process of negative selection, in which thymocytes that react with self antigens are deleted, resulting in peripheral tolerance to self antigens.I9 The studies reported in this paper were undertaken to shed light on the issues of how PCD is induced in immature, mature, and transformed T cells, and how PCD is regulated in vivo to effect the shaping the T cell antigen-specific repertoire. MATERIALS AND METHODS Mice Balbk, BlO.A, and timed pregnant C57BL/6 (B6) mice were obtained from the Frederick Cancer Research Center (Frederick, MD). Antibodies Hamster IgG (HIgG) was purchased from Jackson ImmunoResearch Laboratories, Inc. (West Grove, PA). 145-2C11 (2C11; hamster anti-mouse CD~-E),~O H57-597 (H57; hamster anti-mouse TCR (YP),~' and G7 (rat anti-mouse Thy-1)22 were produced and purified as described.23 F23.1 (anti-V/38)24 and RR-4-7(anti-V/36)25 were used as culture supernatants to stain thymocytes. FITC-GK 1.5 (anti-CD4)26 and biotinylated 2.43 (anti-CD8)27 were kindly provided by Ada Kruisbeek (NIH, Bethesda, MD). Staphylococcal enterotoxin B (SEB) and dexamethasone (Dex) were purchased from Sigma Chemical Co. (St. Louis, MO). CsA was purchased from Sandoz Inc. (East Hanover, NJ). RU-486 was the generous gift of E. E. Baulieu (Universite de Paris-Sud, France). An anti-glucocorticoid receptor (GR) antiserum, aP1, was kindly provided by Bernd Groner (Fridrick Miescher-Institut, Basel, Switzerland). Culture Medium 2B4.11 cells were maintained in RPMI 1640 (Biofluids Inc., Rockville, MD) supplemented with 10% heat-inactivated fetal calf serum, 4 mM glutamine, 10 U/ml penicillin, 150 pg/ml gentamicin, and 5 x M 2-mercaptoethanol (complete medium). Cells 2B4.11 is a cytochrome c-specific T cell hybridoma, a fusion product of the AKR-derived thymoma BW5147 and B1O.A splenic T cells.28 LK 35.2 is MHC class 11-and Fc receptor-bearing B cell Thymocyte Depletion Assay Mice were injected i.p. with control HIgG or anti-TCR antibodies in PBS, using a fixed antibodylmouse weight ratio in a given experiment. Twenty-four or