Thymic Homeostasis Research Articles

Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis

The vitamin A metabolite and transcriptional modulator retinoic acid (RA) is recognized as an important regulator of epithelial cell homeostasis in several tissues. Despite the known importance of the epithelial compartment of the thymus in T cell development and selection, the potential role of RA in the regulation of thymic cortical and medullary epithelial cell homeostasis has yet to be addressed. In this study, using fetal thymus organ cultures, we demonstrate that endogenous RA signaling promotes thymic epithelial cell (TEC) cell-cycle exit and restricts TEC cellularity preferentially in the cortical TEC compartment. Combined gene expression, biochemical, and functional analyses identified mesenchymal cells as the major source of RA in the embryonic thymus. In reaggregate culture experiments, thymic mesenchyme was required for RA-dependent regulation of TEC expansion, highlighting the importance of mesenchyme-derived RA in modulating TEC turnover. The RA-generating potential of mesenchymal cells was selectively maintained within a discrete Ly51(int)gp38(+) subset of Ly51(+) mesenchyme in the adult thymus, suggesting a continual role for mesenchymal cell-derived RA in postnatal TEC homeostasis. These findings identify RA signaling as a novel mechanism by which thymic mesenchyme influences TEC development.

Altered Thymic Function during Interferon Therapy in HCV-Infected Patients

Interferon alpha (IFNα) therapy, despite good efficacy in curing HCV infection, leads to major side effects, in particular inducement of a strong peripheral T-cell lymphocytopenia. We here analyze the early consequences of IFNα therapy on both thymic function and peripheral T-cell homeostasis in patients in the acute or chronic phase of HCV-infection as well as in HIV/HCV co-infected patients. The evolution of T-cell subsets and T-cell homeostasis were estimated by flow cytometry while thymic function was measured through quantification of T-cell receptor excision circles (TREC) and estimation of intrathymic precursor T-cell proliferation during the first four months following the initiation of IFNα therapy. Beginning with the first month of therapy, a profound lymphocytopenia was observed for all T-cell subsets, including naïve T-cells and recent thymic emigrants (RTE), associated with inhibition of intrathymic precursor T-cell proliferation. Interleukin (IL)-7 plasma concentration rapidly dropped while lymphocytopenia progressed. This was neither a consequence of higher consumption of the cytokine nor due to its neutralization by soluble CD127. Decrease in IL-7 plasma concentration under IFNα therapy correlated with the decline in HCV viral load, thymic activity and RTE concentration in blood. These data demonstrate that IFNα-based therapy rapidly impacts on thymopoiesis and, consequently, perturbs T-cell homeostasis. Such a side effect might be detrimental for the continuation of IFNα therapy and may lead to an increased level of infectious risk, in particular in HIV/HCV co-infected patients. Altogether, this study suggests the therapeutic potential of IL-7 in the maintenance of peripheral T-cell homeostasis in IFNα-treated patients.

Omenn Syndrome: inflammation and autoimmunity

Background Omenn Syndrome (OS) is a rare inherited disorder presenting with early-onset generalized erythrodermia, alopecia, chronic diarrhea, lymphoadenopathy, failure to thrive, and recurrent infections. The immunological phenotype is characterized by eosinophilia, virtual absent circulating B cells but elevated IgE serum levels. T cells are normal or increased and display a highly restricted, oligoclonal TCR repertoire. Because of overwhelming infections and loss of proteins, the disease is fatal, unless treated with allogeneic bone marrow transplantation, which is variably successful. We have previously demonstrated that mutations in either RAG1 and RAG2, impairing, but not abolishing, the first steps of V(D)J recombination, are the main cause of this syndrome [1]. Nonetheless, a compelling explanation for the autoimmune features of OS has proven elusive. The pathogenesis is likely multifactorial. We have shown that the reduced thymopoiesis in OS patients is accompanied by defects in thymic epithelial cell maturation and/or homeostasis, impaired expression of autoimmune regulator (aire) protein and poor generation of thymic CD4+CD25 +Foxp3+ natural regulatory T cells [2,3]. While these observations emphasize the potential role of T cell tolerance impairments in sustaining the immune dysregulation of OS, a possible contribution of defects in other immune cells, such as antigen presenting cells, has not been investigated. In addition, numerous questions remain surrounding the disease pathogenesis. To gain insights into the mechanisms underlying autoimmunity, we have recently generated a murine model (the Rag2mouse) carrying in Rag2 gene a mutation responsible for OS in many patients. This mouse model recapitulates the phenotype and many of the clinical manifestations of OS patients [4]. We have used this model to further investigate T and B cell contribution in the pathogenesis of autoimmune manifestations in OS.

Immunoreactive neuropeptides in the cells of human thymus

The study was designed to explore the expression of different neuropeptides, viz. vasoactive intestinal peptide (VIP), calcitonin gene related peptide (CGRP), substance P (SP), bombesin and motilin in the cells of fetal and adult human thymus. Immunohistochemical staining revealed that cortical and medullary thymocytes were labeled by all antibodies, except those specific for motilin. Immunoreactive VIP and SP were observed in the solitary epithelial cells located in the subcapsular/subtrabecular cortex, at the corticomedullary junction and in the medulla. The cells within the subcapsular/subtrabecular monolayer, rare solitary cells in the deep cortex and epithelial cell network in the medulla, were labeled with antibodies to CGRP and bombesin. Hassall?s corpuscles were labeled with all antibodies except that specific for SP. The obtained data obtained testify to the expression of different neuropeptides in human thymic lymphoid and non-lymphoid cells and suggest a role for neuroendocrine hormone-mediated mechanisms in the regulation of thymic homeostasis in humans.

Consideration of strategies for hematopoietic cell transplantation

Bone marrow transplantation has been adoptively transferred from oncology to the treatment of autoimmune disorders. Along with extension of prevalent transplant-related concepts, the assumed mechanism that arrests autoimmunity involves elimination of pathogenic cells and resetting of immune homeostasis. Similar to graft versus tumor (GVT) reactivity, allogeneic transplants are considered to provide a better platform of immunomodulation to induce a graft versus autoimmunity reaction (GVA). It is yet unclear whether recurrence of autoimmunity in both autologous and allogeneic settings reflects relapse of the disease, transplant-associated immune dysfunction or insufficient immune modulation. Possible causes of disease recurrence include reactivation of residual host pathogenic cells and persistence of memory cells, genetic predisposition to autoimmunity and pro-inflammatory characteristics of the target tissues. Most important, there is little evidence that autoimmune disorders are indeed abrogated by current transplant procedures, despite reinstitution of both peripheral and thymic immune homeostasis. It is postulated that non-specific immunosuppressive therapy that precedes and accompanies current bone marrow transplant strategies is detrimental to the active immune process that restores self-tolerance. This proposition refocuses the need to develop strategies of immunomodulation without immunosuppression.

Leptin receptor is expressed in thymus medulla and leptin protects against thymic remodeling during endotoxemia-induced thymus involution

Leptin deficiency in mice results in chronic thymic atrophy, suppressed cell-mediated immunity, and decreased numbers of total lymphocytes, suggesting a key role for the metabolic hormone leptin in regulating thymopoiesis and overall immune homeostasis. Unfortunately, the thymus is highly susceptible to stress-induced acute involution. Prolonged thymus atrophy in stress situations can contribute to peripheral T cell deficiency or inhibit immune reconstitution. Little is known, however, about specific roles for leptin signaling in the thymus or the underlying mechanisms driving thymic involution or thymic recovery after acute stress. We report here that leptin receptor expression is restricted in thymus to medullary epithelial cells. Using a model of endotoxemia-induced acute thymic involution and recovery, we have demonstrated a role for supraphysiologic leptin in protection of thymic epithelial cells (TECs). We also present data in support of our hypothesis that leptin treatment decreases in vivo endotoxemia-induced apoptosis of double positive thymocytes and promotes proliferation of double negative thymocytes through a leptin receptor isoform b-specific mechanism. Furthermore, our studies have revealed that leptin treatment increases thymic expression of interleukin-7, an important soluble thymocyte growth factor produced by medullary TECs. Taken together, these studies support an intrathymic role for the metabolic hormone leptin in maintaining healthy thymic epithelium and promoting thymopoiesis, which is revealed when thymus homeostasis is perturbed by endotoxemia.

Thymocyte-Synthesized Glucocorticoids Play a Role in Thymocyte Homeostasis and Are Down-Regulated by Adrenocorticotropic Hormone

Thymocytes from adult mice synthesize glucocorticoids (GCs), and some data indicate a role for this hormone production in thymic homeostasis. Here we present further support for this view by showing that the dramatic increase in thymocyte number seen after adrenalectomy (ADX) does not correlate with the decrease in systemic GCs but rather with an ACTH-mediated down-regulation of GC synthesis in thymocytes. High ACTH concentrations caused by ADX in wild-type mice down-regulated CYP11B1 mRNA expression, encoding the last enzyme required for corticosterone synthesis and as a consequence reduced GC synthesis in thymocytes. This was not seen in IL-1beta/IL-18 double-knockout mice unable to respond to ADX with high ACTH levels. However, if ADX IL-1beta/IL-18 double-knockout mice were treated with ACTH, this led to a down-regulation of CYP11B1 and GC synthesis in thymocytes. In addition, in vivo treatment of mice with the CYP11B1 antagonist metyrapone, without affecting the systemic corticosterone level, increased thymocyte numbers and in vitro treatment of isolated thymocytes prevented thymocyte loss. Furthermore, in vitro experiments showed that both ACTH and its receptor-induced second-messenger molecule cAMP down-regulated mRNA expression of critical enzymes in GC steroidogenesis and GC synthesis in thymocytes. We conclude that thymocyte-produced GCs are important for the homeostasis of adult mouse thymocytes and that high ACTH level, in contrast to stimulating GC synthesis in the adrenal glands, has the opposite effect in thymocytes.

Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25

Thymic T cell progenitor (TCP) importation is a periodic, gated event that is dependent on the expression of functional P-selectin ligands on TCPs. Occupancy of intrathymic TCP niches is believed to negatively regulate TCP importation, but the nature of this feedback mechanism is not yet resolved. We show that P-selectin and CCL25 are periodically expressed in the thymus and are essential parts of the thymic gate-keeping mechanism. Periodicity of thymic TCP receptivity and the size of the earliest intrathymic TCP pool were dependent on the presence of functional P-selectin ligand on TCPs. Furthermore, we show that the numbers of peripheral blood lymphocytes directly affected thymic P-selectin expression and TCP receptivity. We identified sphingosine-1-phosphate (S1P) as one feedback signal that could mediate influence of the peripheral lymphocyte pool on thymic TCP receptivity. Our findings suggest a model whereby thymic TCP importation is controlled by both early thymic niche occupancy and the peripheral lymphocyte pool via S1P.

Maintenance of a normal thymic microenvironment and T-cell homeostasis require Smad4-mediated signaling in thymic epithelial cells

AbstractSignals mediated by the transforming growth factor-β superfamily of growth factors have been implicated in thymic epithelial cell (TEC) differentiation, homeostasis, and function, but a direct reliance on these signals has not been established. Here we demonstrate that a block in canonical transforming growth factor-β signaling by the loss of Smad4 expression in TECs leads to qualitative changes in TEC function and a progressively disorganized thymic microenvironment. Moreover, the number of thymus resident early T-lineage progenitors is severely reduced in the absence of Smad4 expression in TECs and directly correlates with extensive thymic and peripheral lymphopenia. Our observations hence place Smad4 within the signaling events in TECs that determine total thymus cellularity by controlling the number of early T-lineage progenitors.

Stem cell mobilization in idiopathic steroid-sensitive nephrotic syndrome

Steroid-sensitive nephrotic syndrome (SSNS) is classically thought to be a T-cell disorder. The aim of this study was to examine whether or not thymus homeostasis was affected in SSNS. Mature and naive T cell recent thymic emigrants were quantified in the peripheral blood of nephrotic patients and controls. Because the generation of new T cells by the thymus ultimately depends on hematopoietic stem cells, CD34+ cells were also included in the study. Nineteen patients with SSNS during relapse, 13 with SSNS during proteinuria remission, and 18 controls were studied. Cell-surface markers (CD3, CD4, CD8, CD19, CD16, CD56, CD45RA, CD62L, CD34, and CD38) were analyzed by flow cytometric analysis. T-cell rearrangement excision circles (TRECs) were quantified in CD2+ cells by real-time polymerase chain reaction. Stroma cell-derived factor-1 (SDF-1) genotype and metalloproteinase-9 (MMP-9) plasma levels were also determined. Mature T cells (CD4+ and CD8+), circulating naive T cells (CD62L+ and CD3+ CD62L+), and recent thymic emigrants (CD45RA+) as well as TRECs, that measure thymus production, had a similar level in the three groups of patients. Conversely, CD34+ hematopoietic stem cells displayed a two-fold increase in SSNS patients during relapse either compared with controls or SSNS patients at remission. In addition, compared with controls, SSNS patients at remission displayed (1) a decrease in CD19+ cells (B cells) and (2) an increase in CD16CD56+ cells [natural killer (NK) cells]. In conclusion, thymus homeostasis is not significantly affected in nephrotic patients. Hematopoietic stem-cell mobilization at proteinuria relapse, as well as changes in B and NK cells during remission, suggest that SSNS might be due to a general disturbance of hematopoietic and immune cell trafficking.

Progression of intracranial glioma disrupts thymic homeostasis and induces T-cell apoptosis in vivo.

The thymus is the site where all T-cell precursors develop, mature, and subsequently leave as mature T-cells. Since the mechanisms that mediate and regulate thymic apoptosis are not fully understood, we utilized a syngenic GL261 murine glioma model to further elucidate the fate of T-cells in tumor bearing C57BL/6 mice. First, we found a dramatic reduction in the size of the thymus accompanied by a decrease in thymic cellularity in response to glioma growth in the brains of affected mice. There was a marked reduction of double positive subset and an increase in the frequency of CD4(+) and CD8(+) single positive T-cell subsets. Analysis of double negative thymocytes showed an increase in the accumulation of CD44(+) cells. In contrast, there was a marked loss of CD44 and CD122 expression in CD4(+) and CD8(+) subsets. The growth of intracranial tumors was also associated with decreased levels of HO-1, a mediator of anti-apoptotic function, and increased levels of Notch-1 and its ligand, Jagged-1. To determine whether thymic atrophy could be due to the effect of Notch and its ligand expression by glioma in vivo, we performed a bone marrow transplant experiment. Our results suggest that Notch-1 and its ligand Jagged-1 can induce apoptosis of thymocytes, thereby influencing thymic development, immune system homeostasis, and function of the immune cells in a model of experimental glioma.

Role of hepatocyte growth factor in the thymic involution of tumor-bearing mice. (49.32)

Abstract During mammary tumorigenesis, there is a profound thymus involution associated with a severe depletion of the most abundant subset of thymocytes, CD4+CD8+ immature cells, however, the mechanisms involved in this phenomenon remain to be elucidated. We have previously reported that the thymic involution observed in tumor bearing mice is associated with an early block in T cell maturation. This alteration in thymocyte differentiation might be due to an impaired function of stromal cell microenvironment in this organ. Using the D1-DMBA-3 mammary tumor model we found that IL-7 and IL-15 mRNA, crucial cytokines involved in thymic development and cellular homeostasis respectively, are profoundly down-regulated in the thymuses of tumor hosts. Importantly, the expression of the gene for hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesisand differentiation, is down-regulated in thymuses of tumor bearers. Injection of HGF into mice implanted with the mammary tumor resulted in a partial restoration of the thymus volume and of the levels of IL-7 and IL-15 in this organ. Collectively, our data suggest that HGF may play an important role in the thymic involution in tumor bearing hosts and that the cytokines expressed in the thymus microenvironment may be modulated by this growth factor.

281 Increased Leptin Levels in Children with Infections

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. As a hormone, leptin regulates food intake and basal metabolism, and is sexually dimorphic that is, its serum concentration is higher in females than in males with a similar body fat mass. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 and tumour-necrosis factor. Similar to other pro-inflammatory cytokines, leptin promotes Thelper1 (TH1)-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models. Many studies in animals have demonstrated that leptin levels increase acutely during infection and inflammation. We studied the leptin response to infections in 27 children with bacterial infections mainly respiratory and urinary tract. Serum Amyloid A protein (SAA) and C-reactive protein (CRP) in serum were measured by particle-enhanced immunonephelometric assays (BNProSpec Dade Behring), procalcitonin (PCT) levels were determined by chemiluminescence (Brahms), while leptin levels were measured by an enzymatically amplified two-step sandwich-type immunoassay (DSL). The main results of the study are summarized in the table:Table 1Full size tableLeptin levels increased in all patients independently of their BMI, at diagnosis of the infection and returned to normal levels after treatment. This is an indication of normal expression of leptin genes and leptin receptor and this suggests that leptin is also an inflammatory marker. Similar results have been described in patients with sepsis, whereas the non-increase of leptin levels was associated with increased mortality. The secretion of leptin in the first hours of inflammation in children is stimulated by the endotoxins of bacteria as it has been shown in animal models. Leptin seems to play an important role being part of the cytokine network and modulating the inflammatory-immune response and the host defense mechanisms.

Benznidazole Therapy inTrypanosoma cruzi-Infected Mice Blocks Thymic Involution and Apoptosis of CD4+CD8+Double-Positive Thymocytes

Several alterations involving peripheral lymphoid organs have been extensively described after experimental Trypanosoma cruzi infection. Thymic involution occurs as well in infected mice, with both structural and functional alterations in the organ. Despite these abnormalities, specific immune response proceeds to control parasitemia and the participation of T lymphocytes is essential. However, there are relatively few studies on the impact of benznidazole (N-benzyl-2-nitroimidazole acetamide) upon this response. In this present work, we decided to evaluate the impact of benznidazole treatment upon the thymus involution following acute T. cruzi infection in mice. We have provided evidence that benznidazole treatment controls the severe abnormalities seen in the thymus due to T. cruzi infection. The thymocyte loss related to the depletion of double-positive CD4(+)CD8(+) thymocytes was clearly prevented, corroborating the idea that the mechanism responsible for the prevention of thymus involution is related to the decrease of apoptosis rate in this subset after benznidazole treatment. Furthermore, we demonstrated the prevention of enhanced extracellular matrix deposition in the thymus. In conclusion, the preservation of thymus homeostasis, even though partial, was accomplished after benznidazole treatment. Our data are consistent with the notion that different outcomes of T. cruzi infection may be linked to differences in the parasite load concomitant to fine tuning of the host immune response.

Leptin in Immunology

Leptin is an adipokine which conveys information on energy availability. In humans, leptin influences energy homeostasis and regulates neuroendocrine function primarily in states of energy deficiency. As a cytokine, leptin also affects thymic homeostasis and, similar to other proinflammatory cytokines, leptin promotes Th1 cell differentiation and cytokine production. We review herein recent advances on the role of leptin in the pathophysiology of immune responses.

Restoration of Thymic Homeostasis in a Tumor-Bearing Host by in Vivo Administration of Medicinal Herb Tinospora Cordifolia

In vivo administration of alcoholic extract of medicinal plant Tinospora cordifolia (TC) to mice bearing a spontaneous T cell lymphoma designated as Dalton’s lymphoma prevented tumor growth-dependent regression of thymus. TC was found to augment proliferation of thymocytes with a concomitant decrease in thymocyte apoptosis. It also resulted in a decrease in the number of Hassal’s corpuscles. Restoration of thymus homeostasis was caused by TC-dependent augmentation in production of thymocyte growth promoting cytokines Interleukin-2 and Interferon-gamma from thymocytes. TC was found to downregulate thymocyte apoptosis by modulation of Caspase pathway. TC administration retarded tumor growth and prolonged survival of tumor-bearing mice. The possible mechanisms are discussed.

Insulin-Like Growth Factor I Is a Positive Regulator of Thymic Function.

The thymus is important in the recovery and maintenance of T-cell populations following hematopoietic stem cell transplantation. Neuroendocrine growth factors have been implicated in the regulation of thymocyte development and overall thymic function through direct effects on developing thymocytes and/or modulation of supporting thymic stroma. Insulin-like growth factor 1 (IGF-1) is a ubiquitously expressed mediator of cellular anabolic function that has been shown to affect the growth of primary and secondary immune organs. We present evidence supporting the role of IGF-1 as a regulator of thymic function in vivo. Recombinant human IGF-1 was administered into healthy young adult mice by continuous infusion for up to four weeks at a dose of 100 ug/day (5 mg/kg/day). During this period, thymic function was measured by multiple parameters including thymocyte number, thymocyte subset composition, thymic T-cell rearrangement circle (TREC) content, proliferation and developmental kinetics as measured by BrdU incorporation, peripheral naïve T-cell subsets, and peripheral TREC content. Two-week infusions of IGF-1 resulted in significant increases in thymic size, cellularity, and thymic TREC numbers. Within the earliest lineage-negative thymocyte subpopulations defined by CD44 and CD25 co-expression patterns, significant increases in the DN2 through DN4 subpopulations were observed. CD4+CD8+, CD4+CD8-, and CD4-CD8+ thymic populations were also uniformly increased with IGF-1 treatment. BrdU incorporation was increased in all thymocyte subsets with IGF-1 administration, suggesting a stimulatory effect of IGF-1 on thymocyte proliferation and developmental kinetics. In peripheral T-cell populations, significant increases in the number of CD4+ and CD8+ naïve cells were observed after four weeks of IGF-1 treatment. The expansion of peripheral naïve cell populations occurred in the absence of increased cell division as measured by Ki67 expression. On the other hand, significant increases in total peripheral TREC numbers were observed at this time, indicating an increase in the number of recent thymic emigrants with IGF-1 administration. IGF-1 receptor (IGF-1R) is expressed on both thymocytes and peripheral T-cells. Mice constitutively homozygous for null mutations of IGF-1R die at birth. Consequently, to assess the role of IGF-1R signaling on thymic function and T-cell homeostasis, mice lacking IGF-1R specifically on thymocytes and T-cells were generated by cre recombinase mediated deletion of the IGF-1R high-affinity binding site (LCK-Cre/lox-IGF1R). Compared to cre-negative littermates, LCK-Cre/lox-IGF1R mice exhibited a 50% decrease in thymocyte cellularity that is due almost entirely to decreases in the CD4+CD8+ double-positive thymocyte population and in the lineage-negative DN4 subpopulation. The size of the CD4+CD8- and CD4-CD8+ thymocyte populations were not affected. Thymic TREC numbers were also decreased by 50%. Diminished thymic output in LCK-Cre/lox-IGF1R mice was manifested by a decrease in the size of splenic naïve CD4+ and CD8+ populations and splenic TREC numbers. These results demonstrate that: 1) administration of IGF-1 enhances thymic function through the expansion of thymocyte subpopulations and thymic output; and 2) IGF-1R signaling is important in the maintenance of thymocyte and peripheral T-cell populations. These findings support the concept of IGF-1 as a potentially useful agent in facilitating T-cell reconstitution following hematopoietic stem cell transplant.

The weight of leptin in immunity.

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. As a hormone, leptin regulates food intake and basal metabolism, and is sexually dimorphic - that is, its serum concentration is higher in females than in males with a similar body fat mass. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 and tumour-necrosis factor. Similar to other pro-inflammatory cytokines, leptin promotes T helper 1 (TH1)-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models of disease. Here, we review the advances and controversy for a role of leptin in the pathophysiology of immune responses.

Glucocorticoids delay age-associated thymic involution through directly affecting the thymocytes.

After puberty, the thymus undergoes a dramatic loss in size, resulting in a reduction in the number of thymocytes, a phenomenon termed age-associated thymic involution. The factors regulating this process are poorly understood. We investigated the role of endogenous glucocorticoids (GCs) in this process by studying transgenic mice with increased GC sensitivity restricted to the T-cell lineage due to overexpression of a GC-receptor transgene under the control of the proximal lck promoter. Surprisingly, in these transgenic mice, the age-associated thymic involution did not start until after 6 months of age, demonstrating that endogenous GCs through directly affecting the thymocytes delay the age-associated thymic involution process. The delayed age-associated thymic involution resulted in a significantly higher number of thymocytes in transgenic mice, compared with wild-type mice at 6 months of age or older. The higher number of thymocytes was associated with increased percentage of cycling double-negative and single-positive thymocytes, whereas thymic apoptosis was unaffected. The above effects of GCs were restricted to the thymocytes and were not reflected on the peripheral T cells, in which GCs suppressed the number of peripheral T cells in aged transgenic mice, demonstrating that thymocytes and T cells are differentially regulated by GCs. Furthermore, CD4(+) T cells were more affected than CD8(+) T cells, resulting in a decrease in the CD4/CD8 T-cell ratio. In summary, our results reveal novel biological effects of endogenous GCs on thymic involution and T-cell homeostasis in aged mice.

Thymus-derived glucocorticoids are insufficient for normal thymus homeostasis in the adult mouse

BackgroundIt is unclear if thymus-derived glucocorticoids reach sufficient local concentrations to support normal thymus homeostasis, or if adrenal-derived glucocorticoids from the circulation are required. Modern approaches to this issue (transgenic mice that under or over express glucocorticoid receptor in the thymus) have yielded irreconcilably contradictory results, suggesting fundamental problems with one or more the transgenic mouse strains used. In the present study, a more direct approach was used, in which mice were adrenalectomized with or without restoration of circulating corticosterone using timed release pellets. Reversal of the increased number of thymocytes caused by adrenalectomy following restoration of physiological corticosterone concentrations would indicate that corticosterone is the major adrenal product involved in thymic homeostasis.ResultsA clear relationship was observed between systemic corticosterone concentration, thymus cell number, and percentage of apoptotic thymocytes. Physiological concentrations of corticosterone in adrenalectomized mice restored thymus cell number to normal values and revealed differential sensitivity of thymocyte subpopulations to physiological and stress-inducible corticosterone concentrations.ConclusionThis indicates that thymus-derived glucocorticoids are not sufficient to maintain normal levels of death by neglect in the thymus, but that apoptosis and possibly other mechanisms induced by physiological, non stress-induced levels of adrenal-derived corticosterone are responsible for keeping the total number of thymocytes within the normal range.