Thymic Growth Research Articles

A Mechanistic Model for Naive CD4 T Cell Homeostasis in Healthy Adults and Children

The size and composition of the T lymphocyte compartment is subject to strict homeostatic regulation and is remarkably stable throughout life in spite of variable dynamics in cell production and death during T cell development and immune responses. Homeostasis is achieved by careful orchestration of lymphocyte survival and cell division. New T cells are generated from the thymus and the number of peripheral T cells is regulated by controlling survival and proliferation. How these processes combine is however very complex. Thymic output increases in the first year of life and then decreases but is crucial for establishing repertoire diversity. Proliferation of new naive T cells plays a crucial role for maintaining numbers but at a potential cost to TCR repertoire diversity. A mechanistic two-compartment model of T cell homeostasis is described here that includes specific terms for thymic output, cell proliferation, and cell death of both resting and dividing cells. The model successfully predicts the homeostatic set point for T cells in adults and identifies variables that determine the total number of T cells. It also accurately predicts T cell numbers in children in early life despite rapid changes in thymic output and growth over this period.

Normal Thymic Size and Low Rate of Infections in Human Donor Milk Fed HIV-Exposed Uninfected Infants from Birth to 18 Months of Age

Objective. To evaluate the immune function in HIV-exposed uninfected (HIV-EU) infants fed human donor milk. Methods. Ultrasound-obtained thymic index (Ti), T-lymphocyte subsets, and the number of infections were examined from birth to 18 months of age in 18 HIV-EU infants. The infants were compared to a cohort of 47 term, HIV-unexposed breastfed or formula-fed infants. Results. The thymic size at 12 months of age was not significantly different between the HIV-EU group and the control infants (P = 0.56). At 4 months of age, the HIV-EU infants had significantly fewer infections than the control infants (P < 0.001). Furthermore, in the control group, the infants exclusively breastfed at 4 months of age had significantly fewer infections at 8 months when compared to age-matched formula-fed infants (P = 0.001). Conclusion. HIV-EU infants fed human donor milk have normal growth of thymus and contract fewer infections than other healthy infants. This finding along with fewer infections in exclusively breastfed infants compared to formula-fed infants supports the beneficial effect of human milk on the immune system. We suggest, when breastfeeding is not possible, that providing human donor milk to vulnerable groups of infants will be beneficial for their maturing immune system.

Impaired fetal thymic growth precedes clinical preeclampsia: a case–control study

In preeclampsia the maternal adaptive immune system undergoes specific changes, which are different from the physiological processes associated with healthy pregnancy. Whether preeclampsia also affects the fetal immune system is difficult to investigate, due to limited access to the fetus. We hypothesized that if preeclampsia affects the fetal adaptive immune system this might be associated with early changes in thymic growth. In this case–control study, 53 preeclamptic and 120 healthy control pregnancies were matched for maternal age, gestational age and smoking. Fetal thymus diameter was measured as the greatest width perpendicular to a line connecting sternum and spine based on ultrasound images taken at 17–21 weeks gestation. Independent of fetal and maternal anthropometric measures, thymuses were found to be smaller in preeclamptic pregnancies than healthy controls (16.2mm versus 18.3mm, respectively, mean difference=2.1mm, 95% CI: 0.8–3.3, p<0.001), and the odds of developing preeclampsia was estimated to be 0.72 (95% CI: 0.60–0.86, p<0.001) lower for each 1mm increase in thymus diameter. There was no correlation between the onset of preeclampsia and fetal thymus size. This is the first study to suggest that fetal thymus growth is reduced before the clinical onset of preeclampsia and precedes any described fetal anomalies or maternal immunological changes associated with preeclampsia. We propose that the fetal adaptive immune system is either passively affected by maternal processes preceding clinical preeclampsia or is actively involved in initiating preeclampsia in later pregnancy.

Síndrome de microdeleción 22q11: manifestaciones cardiorrespiratorias y utilidad de la fibrobroncoscopia

The 22q11 deletion syndrome is a frequent contiguous-gene deletion syndrome. This disorder has a broad spectrum of phenotypic manifestations. It includes various syndromes such as DiGeorge syndrome.The most frequent clinical manifestations are congenital cardiac defects, characteristic facies, palate malformations, hypoparathyroidism, immunodeficiency due to thymic hypoplasia, growth retardation, and behavioural and psychiatric problems.Among the symptoms observed, many patients suffer from respiratory insufficiency or failure. The origin is often multifactorial. Structural airway abnormalities are frequently found in this syndrome. In many of these patients the malformation is mild or non-existent, and remains asymptomatic. However, in some cases it can cause a severe respiratory insufficiency, being diagnosed when other disorders are ruled out.These cases illustrate the importance of early visualisation of the airway by fibrobronchoscopy in the management of the patient with 22q11 deletion syndrome who has recurrent respiratory difficulties.

Steroid Receptor Expression in Thymomas and Thymic Carcinomas

PURPOSE: Although protein expressions of glucocorticoid receptor (GR), estrogen receptors (ERα and ERβ), progesterone receptor A (PgR-A), and androgen receptor (AR) were shown to play roles in the growth and differentiation of normal thymus and thymic tumors, their association with patient characteristics and prognosis is undetermined yet. The purpose of this study is to disclose the steroid receptors expression status in thymic tumors.

Low thymic size in preterm infants in the neonatal intensive care unit, a possible marker of infection? A prospective study from birth to 1 year of age

To study the growth of the thymus in preterm infants. Ultrasonographic thymic size (Ti) was studied in 80 preterm infants (gestational age 24-36 weeks) from birth to discharge from the neonatal intensive care unit (NICU). Thirty-three of these infants were followed to 1 year of age. At birth, the median Ti was 5.2 compared with 11.8 in term infants. At discharge, the median Ti was 10.0 and not significantly different from Ti in term infants at birth (p = 0.22). The size of the thymus was significantly associated with postmenstrual age and weight (both p < 0.01). Infections during admission were negatively associated with the size of the thymus (p < 0.01). During the first 3 months after discharge, preterm infants had a significantly higher frequency of infections than did term infants (p = 0.002); hereafter, the preterm infants had significantly fewer infections than term infants (p = 0.002). The median Ti in preterm infants and term infants at 1 year of age was 21.1 and 17.3, respectively. This difference was not statistically significant (p = 0.41). Growth of thymus was not compromised by preterm birth. Ti is negatively associated with the frequency of infections in preterm neonates submitted to NICU.

Steroid receptor expression in thymomas and thymic carcinomas

Although protein expressions of glucocorticoid receptor (GR), estrogen receptors (ERα and ERβ), progesterone receptor A (PgR-A), and androgen receptor (AR) were shown to play roles in the growth and differentiation of normal thymus and thymic tumors, to the authors' knowledge their association with patient characteristics and prognosis has yet to be determined. A series of 140 thymic epithelial tumors (57 type A + AB thymomas, 40 type B1 + B2 thymomas, 6 type B3 thymomas, and 37 thymic carcinomas) were examined for GR, ERα, ERβ, PgR-A, and AR expression using immunohistochemistry. In addition, the correlation between expression of these hormone receptors and clinicopathologic factors and overall survival (OS) was assessed. GR and ERβ demonstrated a high rate of expression in thymomas and thymic carcinomas (82.9% and 76.4%, respectively), whereas rates of ERα, PgR-A, and AR expression were low (13.6%, 0.71%, and 23.6%, respectively). A significant correlation (P < .05) was found between ERα expression and tumor size and between ERβ expression and tumor stage. Multivariate analyses revealed that histologic subtype (P = .0039), tumor stage (P = .0012), and GR expression (P = .0025) were significantly correlated with the 10-year OS rate. GR and ERβ demonstrated high rates of expression in thymomas and thymic carcinomas. Furthermore, multivariate analysis revealed that GR expression was associated with better prognosis in patients with surgically resected thymomas and thymic carcinomas.

Ultrasonographic Evaluation of Thymus in Holstein Calves and Heifers and its Diagnostic Application

This study was performed to evaluate the cross section of the thymus in 46 clinically healthy Holstein calves and heifers from birth to 100 weeks of age and 8 age-matched affected animals with chronic bronchopneumonia by ultrasonography. The cross sectional area of the thymus increased in healthy calves and heifers from birth to 31 weeks of age, peaked around 35 weeks of age, and then decreased until 100 weeks after birth. A positive correlation (r = 0.74, P < 0.05) was found between the area in cross section and the weight of the whole thymus in calves and heifers with chronic bronchopneumonia. The cross- sectional areas of the thymus were significantly (P < 0.05) lowered in animals with chronic bronchopneumonia. The cross sections of thymus in clinically healthy calves at 2 weeks of age and heifers at 34 weeks and 87 weeks of age were hypoechoic, moderately hyperechoic and hyperechoic, respectively. The observation of thymus by ultrasonography seems to be an effective tool for estimating the size of the thymus objectively in Holstein calves and heifers from birth to 100 weeks of age. The results of this study prove the approach to be useful and applicable to monitor the growth of thymus in Holstein calves and heifers and their association with chronic pneumonia.

CHANGES IN THYMIC GROWTH HORMONE DURING CHICKEN DEVELOPMENT

Event Abstract Back to Event CHANGES IN THYMIC GROWTH HORMONE DURING CHICKEN DEVELOPMENT Adriana J. Rodríguez-Méndez1, 2, Martha E. Carranza1, Carlos Arámburo1 and Maricela Luna1* 1 Universidad Nacional Autonoma de Mexico, Institute of Neurobiology, Dept. of Molecular and Cellular Neurobiology, Mexico 2 Universidad Autónoma de Querétaro, Facultad de Medicina, Mexico It has been shown that growth hormone (GH) is expressed in lymphoid tissues where it may have a role as an autocrine/paracrine factor. Here we studied developmental changes in the GH expression, distribution and isoform patterns in the chicken thymus. The expression and distribution of GH mRNA and GH were analyzed by in situ hybridization using a full-length DIG-labeled riboprobe (690 bp) and by immunohistochemistry. GH-positive signals were observed mainly in lymphocytes within the cortex, although some epithelial, dendritic-like cells and macrophages within the medulla also showed signal. While the GH cDNA obtained from the immune system was identical in sequence to that in the pituitary, the thymic GH immunoreactivity (GH-IR) was associated with proteins of different molecular size (10, 17, 26, 28, 30, 34, 36, 40, 42, 44, 48, 50, and 58 kDa). Variants of 34-40 kDa (50%) were abundant in embryonic thymus, whereas the 17 kDa isoform (60%) was predominant in post-hatching chicks (under reducing-conditions), except at 2 weeks (30%). GH concentration (as determined by ELISA) in embryonic stages was 35 ng/mg protein and a significant increase was detected at 2-4 weeks (80 ng/mg protein), GH concentration decreased again at 10 and 20 weeks of age (50 and 40 ng/mg protein, respectively). GH concentrations showed changes in the thymus, plasma, and pituitary 8 h after 4 week-old chickens were treated with an i.v. injection of lipopolysaccharide (LPS, 5 mg/kg). The results showed a significant increase in thymic GH against control (2-fold), which indicates that local expression of GH can be regulated during the immune response against this endotoxin. These results suggest that local expression of GH may be involved as an autocrine/paracrine factor during development and functional response in the thymus. Acknowledgements Supported by CONACYT [60296N & 161791] and PAPIIT-UNAM [IN210209] grants Keywords: autocrine/paracrine mechanisms, extrapituitary growth hormone, Growth hormone variants, lipopolysaccharide endotoxin, thymic growth hormone, Thymus Conference: NASCE 2011: The inaugural meeting of the North American Society for Comparative Endocrinology, Ann Arbor, United States, 13 Jul - 16 Jul, 2011. Presentation Type: Poster Topic: Abstracts Citation: Rodríguez-Méndez AJ, Carranza ME, Arámburo C and Luna M (2011). CHANGES IN THYMIC GROWTH HORMONE DURING CHICKEN DEVELOPMENT. Front. Endocrinol. Conference Abstract: NASCE 2011: The inaugural meeting of the North American Society for Comparative Endocrinology. doi: 10.3389/conf.fendo.2011.04.00069 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 23 Jul 2011; Published Online: 09 Aug 2011. * Correspondence: Dr. Maricela Luna, Universidad Nacional Autonoma de Mexico, Institute of Neurobiology, Dept. of Molecular and Cellular Neurobiology, Queretaro, Queretaro, 76230, Mexico, lunam@servidor.unam.mx Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract Supplemental Data The Authors in Frontiers Adriana J Rodríguez-Méndez Martha E Carranza Carlos Arámburo Maricela Luna Google Adriana J Rodríguez-Méndez Martha E Carranza Carlos Arámburo Maricela Luna Google Scholar Adriana J Rodríguez-Méndez Martha E Carranza Carlos Arámburo Maricela Luna PubMed Adriana J Rodríguez-Méndez Martha E Carranza Carlos Arámburo Maricela Luna Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Postnatal Development of Hypoplastic Thymus in Semi-Lethal Dwarf pet/pet Males

The petit rat (pet/pet) is a new semi-lethal dwarf mutant with anomalies in the thymus and testes, defects inherited as a single autosomal recessive trait. At birth, these pet/pet rats show low birth weight and extremely small thymuses; at 140 days of age, their thymuses show abnormal involution. In the present study, we examined early postnatal development of hypoplastic pet/pet thymuses. In addition to being hypoplastic at birth, pet/pet thymus growth was almost completely impaired during the early postnatal period. As shown by cellular incorporation of BrdU, the mitotic activity was lower in pet/pet than in normal thymuses, and terminal deoxynucleotidyl transferase dUTP nick end labeling assays showed that apoptosis occurred more often in pet/pet than in normal thymus cells during the first few days after birth. These results indicate that postnatal development of the hypoplastic pet/pet thymus is defective due to the reduced proliferation and increased apoptosis of thymic cells.

Effects of hypophyseal or thymic allograft on thymus development in partially decerebrate chicken embryos: expression of PCNA and CD3 markers

Changes in chicken embryo thymus after partial decerebration (including the hypophysis) and after hypophyseal or thymic allograft were investigated. Chicken embryos were partially decerebrated at 36–40 h of incubation and on day 12 received a hypophysis or a thymus allograft from 18-day-old donor embryos. The thymuses of normal, sham-operated and partially decerebrate embryos were collected on day 12 and 18. The thymuses of the grafted embryos were collected on day 18. The samples were examined with histological method and tested for the anti-PCNA and anti-CD3 immune-reactions. After partial decerebration, the thymic cortical and medullary compartments diminished markedly in size. Anti-PCNA and anti-CD3 revealed a reduced immunereaction, verified also by statistical analysis. In hypophyseal or grafted embryos, the thymic morphological compartments improved, the anti-PCNA and anti-CD3 immune-reactions recovered much better after the thymic graft, probably due to the thymic growth factors and also by an emigration of thymocytes from the same grafted thymus.

Early-life nutrition influences thymic growth in male mice that may be related to the regulation of longevity.

Nutrition and growth rate during early life can influence later health and lifespan. We have demonstrated previously that low birthweight, resulting from maternal protein restriction during pregnancy followed by catch-up growth in rodents, was associated with shortened lifespan, whereas protein restriction and slow growth during lactation increased lifespan. The underlying mechanisms by which these differences arise are unknown. In the present study, we report that maternal protein restriction in mice influences thymic growth in early adult life. Offspring of dams fed a low-protein diet during lactation (PLP offspring) had significant thymic growth from 21 days to 12 weeks of age, whereas this was not observed in control mice or offspring of dams fed a low-protein diet during pregnancy (recuperated offspring). PCNA (proliferating-cell nuclear antigen) and SIRT1 (silent information regulator 1) protein levels at 21 days of age were significantly higher in the thymus from both PLP mice (P<0.001 and P<0.05 respectively) and recuperated mice (P<0.001 and P<0.01 respectively) compared with controls. At 12 weeks, PLP mice maintained a higher SIRT1 level, whereas PCNA was decreased in the thymus from recuperated offspring. This suggests that mitotic activity was initially enhanced in the thymus from both PLP and recuperated offspring, but remained sustained into adulthood only in PLP mice. The differential mitotic activity in the thymus from PLP and recuperated mice appeared to be influenced by changes in sex hormone concentrations and the expression of p53, p16, the androgen receptor, IL-7 (interleukin-7) and the IL-7 receptor. In conclusion, differential thymic growth may contribute to the regulation of longevity by maternal diet.

Role of CRTAM during mouse early T lymphocytes development

CRTAM was reported as a novel receptor expressed in activated NKT and CD8 T lymphocytes. However, we have recently shown that it is also expressed in several non-immune tissues. In opposition to what has been stated for lymphoid cells, CRTAM expression is constitutive in epithelia, suggesting a role in cell–cell interactions. Given the importance of cell interactions during T lymphocyte development, we evaluated CRTAM during T lymphocyte ontogeny. Here we show that CRTAM has an unexpected constitutive expression in adult thymocytes and, remarkably, it is sustained during all stages of thymocyte development. CRTAM expression is restricted to CD8 and all DN subpopulations, with a consistent pattern from E13.5 stage to adult mice. Blocking CRTAM interaction with CADM1 impairs thymus growth, uncovering a novel role in thymus development, with a consequent impact in thymocyte maturation. Thus, CRTAM interaction with CADM1 is involved in structural maintenance of the thymic lobes.

Elevated Proportions of Recent Thymic Emigrants in Children and Adolescents with Type 1 Diabetes

It is unclear, whether pediatric patients with type 1 diabetes (T1DM) show immunological alterations typically found in autoimmune conditions resembling immune dysfunction of the thymus, such as decrease of naïve T cells, lower T cell receptor excision circle (TREC) numbers, telomeric erosion, and diminished interleukin-7 (IL-7) levels. Furthermore, it is unknown, whether long-term therapy with insulin, a thymic growth factor, interferes with these changes. Therefore, the aim of this study was to analyze the quantity of the naïve T cell subset and its TREC content, relative telomere length (RTL) of naïve T cells, and peripheral IL-7 levels in patients with recent-onset T1DM (n = 5), long-standing T1DM (n = 33), and age-matched healthy donors (HD) (n = 37). In long-standing T1DM, TREC numbers/CD8+CD45RA+ T cells were enhanced (p < 0.01) compared to HD and correlated with disease duration (p < 0.02), an independent factor for increased thymic output (p < 0.01), and insulin dosage at blood withdrawal (p < 0.05). IL-7 serum levels were elevated in long-standing T1DM (p < 0.001) and positively correlated with TREC numbers (p < 0.01) and disease duration (p < 0.0001). RTLs in CD8+CD45RA+ T cells were significantly increased compared to HD (p < 0.02). Our data suggest that longterm insulin therapy may serve as a driving factor for thymic function and rejuvenation of the naïve T cell compartment. The ability of the immune system to reconstitute the naïve T cell compartment under well-adjusted insulin therapy may be of major importance for recognition of new antigens, response to vaccinations, and defense of infectious complications.

VEGF-mediated cross-talk within the neonatal murine thymus

AbstractAlthough the mechanisms of cross-talk that regulate the hematopoietic and epithelial compartments of the thymus are well established, the interactions of these compartments with the thymic endothelium have been largely ignored. Current understanding of the thymic vasculature is based on studies of adult thymus. We show that the neonatal period represents a unique phase of thymic growth and differentiation, marked by endothelium that is organized as primitive, dense networks of capillaries dependent on vascular endothelial growth factor (VEGF). VEGF dependence in neonates is mediated by significantly higher levels of both VEGF production and endothelial VEGF receptor 2 (VEGF-R2) expression than in the adult thymus. VEGF is expressed locally in the neonatal thymus by immature, CD4−CD8− “double negative” (DN) thymocytes and thymic epithelium. Relative to adult thymus, the neonatal thymus has greater thymocyte proliferation, and a predominance of immature thymocytes and cortical thymic epithelial cells (cTECs). Inhibition of VEGF signaling during the neonatal period results in rapid loss of the dense capillaries in the thymus and a marked reduction in the number of thymocytes. These data demonstrate that, during the early postnatal period, VEGF mediates cross-talk between the thymocyte and endothelial compartments of the thymus.

An Epithelial Progenitor Pool Regulates Thymus Growth

Thymic epithelium provides an essential cellular substrate for T cell development and selection. Gradual age-associated thymic atrophy leads to a reduction in functional thymic tissue and a decline in de novo T cell generation. Development of strategies tailored toward regeneration of thymic tissue provides an important possibility to improve immune function in elderly individuals and increase the capacity for immune recovery in patients having undergone bone marrow transfer following immunoablative therapies. In this study we show that restriction of the size of the functional thymic epithelial progenitor pool affects the number of mature thymic epithelial cells. Using an embryo fusion chimera-based approach, we demonstrate a reduction in the total number of both embryonic and adult thymic epithelium, which relates to the initial size of the progenitor cell pool. The inability of thymic epithelial progenitor cells to undergo sufficient compensatory proliferation to rescue the deficit in progenitor numbers suggests that in addition to extrinsic regulation of thymus growth by provision of growth factors, intrinsic factors such as a proliferative restriction of thymic epithelial progenitors and availability of progenitor cell niches may limit thymic epithelial recovery. Collectively, our data demonstrate an important level of regulation of thymic growth and recovery at the thymic epithelial progenitor level, providing an important consideration for developing methods targeted toward inducing thymic regeneration.

Associations of Insulin‐Like Growth Factor (IGF)–I and IGF‐Binding Protein–3 with HIV Disease Progression in Women

The insulin-like growth factor (IGF) axis has been hypothesized to influence the rate of human immunodeficiency virus (HIV) disease progression. This premise is based largely on laboratory models showing that IGF-I stimulates thymic growth and increases lymphocyte numbers and that IGF-binding protein (IGFBP)-3 has an opposing effect, inhibiting hematopoietic stem cell development. We studied 1422 HIV-infected women enrolled in a large cohort that entailed semiannual follow-up (initiated in 1994). Baseline serum samples were tested for IGF-I and IGFBP-3 to determine their associations with incident clinical acquired immunodeficiency syndrome (AIDS) and CD4+ T cell count decline prior to April 1996 (before the era of highly active antiretroviral therapy [HAART]). Low IGF-I levels (Ptrend= .02) and high IGFBP-3 levels (Ptrend= .02) were associated with rapid CD4+ T cell count decline. Only IGFBP-3, however, was significantly associated with AIDS incidence (hazard ratio for highest vs. lowest quartile, 2.65 [95% confidence interval, 1.30-5.42]; Ptrend= .02) in multivariable models. These findings suggest that serum levels of IGFBP-3 (and possibly IGF-I) are associated with the rate of HIV disease progression in women and, more broadly, that interindividual heterogeneity in the IGF axis may influence HIV pathogenesis. If correct, the IGF axis could be a target for interventions to slow HIV disease progression and extend the time before use of HAART becomes necessary.

Effects of corticosterone treatment on growth, development, and the corticosterone response to handling in young Japanese quail ( Coturnix coturnix japonica)

Corticosterone, a glucocorticoid secreted during stress responses, has a range of actions that help birds respond to stressors. Although effects of corticosterone treatment have been described in several avian species, the impacts of defined increases in plasma corticosterone on early development and on corticosterone stress responses are little known. These issues were addressed by providing quail with different doses of corticosterone in drinking water from days 8 to 38 post-hatch. The corticosterone dose consumed by each bird during treatment days 15–30 was calculated by measuring water intake. The corticosterone dose was inversely, but weakly, correlated with weights of the bursa, thymus, spleen, liver, testes, oviduct, muscle, and body, and positively correlated with peritoneal fat deposition. When birds were divided into groups based on their corticosterone intake, weights of the spleen, thymus, bursa, muscle, testes, and oviduct were significantly reduced in birds receiving the highest doses; with the exception of muscle, similar reductions were also observed in birds receiving medium doses, and thymic growth was inhibited in birds receiving low doses. The acute corticosterone stress response was measured by handling birds for 15 min. Plasma corticosterone was transiently increased at 15 min in control birds in response to the handling stressor. Some birds consuming low doses of corticosterone had corticosterone responses similar to control birds. Initial corticosterone concentrations were elevated in birds consuming higher doses of corticosterone. Plasma corticosterone in these birds decreased from 0 to 15 min, then increased from 15 to 30 min. The initial decrease could be due to corticosterone clearance, whilst the increase could indicate that the birds had a greater response than control birds to isolation as a stressor. Corticosterone treatment may have reduced the strength of corticosterone negative feedback within the hypothalamo-pituitary–adrenal axis. The results indicate that individuals and organs differ in their sensitivity to corticosterone. Moreover, elevated plasma corticosterone may disrupt the acute corticosterone stress response, and may thus reduce the ability of birds to cope with stressors.

PDGFRα-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches

AbstractThe thymus provides a specialized site for the production of T cells capable of recognizing foreign antigens in the context of self–major histocompatibility complex (MHC) molecules. During development, the thymus arises from an epithelial rudiment containing bipotent progenitors that differentiate into distinct cortical and medullary epithelial cells to regulate the maturation and selection of self-tolerant CD4+ and CD8+ T cells. In addition to their differentiation, thymic epithelial cells undergo cellular expansion to ensure that sufficient intrathymic cellular niches are available to support the large number of immature thymocytes required to form a self-tolerant T-cell pool. Thus, intrathymic T-cell production is intimately linked to the formation and availability of niches within thymic microenvironments. Here, we show the increase in intrathymic niches caused by the proliferation of the epithelium in the developing thymus is temporally regulated, and correlates with the presence of a population of fetal thymic mesenchyme defined by platelet-derived growth factor receptor α (PDGFRα) expression. Depletion of PDGFRα+ mesenchyme from embryonic thymi prior to their transplantation to ectopic sites results in the formation of functional yet hypoplastic thymic tissue. In summary, we highlight a specialized role for PDGFRα+ fetal mesenchyme in the thymus by determining availability of thymic niches through the regulation of thymic epithelial proliferation.

Genetic mosaics reveal both cell-autonomous and cell-nonautonomous function of murine p27Kip1.

Loss of the cyclin-dependent kinase inhibitor p27(Kip1) leads to an overall increase in animal growth, pituitary tumors, and hyperplasia of hematopoietic organs, yet it is unknown whether all cells function autonomously in response to p27(Kip1) activity or whether certain cells take cues from their neighbors. In addition, there is currently no genetic evidence that tumor suppression by p27(Kip1) is cell-autonomous because biallelic gene inactivation is absent from tumors arising in p27(Kip1) hemizygous mice. We have addressed these questions with tissue-specific targeted mouse mutants and radiation chimeras. Our results indicate that the suppression of pars intermedia pituitary tumors by p27(Kip1) is cell-autonomous and does not contribute to overgrowth or infertility phenotypes. In contrast, suppression of spleen growth and hematopoietic progenitor expansion is a consequence of p27(Kip1) function external to the hematopoietic compartment. Likewise, p27(Kip1) suppresses thymocyte hyperplasia through a cell-nonautonomous mechanism. The interaction of p27(Kip1) loss with epithelial cell-specific cyclin-dependent kinase 4 overexpression identifies the thymic epithelium as a relevant site of p27(Kip1) activity for the regulation of thymus growth.