Direct demonstration of the infiltration of murine central nervous system by Pgp-1/CD44high CD45RB(low) CD4+ T cells that induce experimental allergic encephalomyelitis.

In experimental allergic encephalomyelitis (EAE), autoimmune T cells infiltrate the central nervous system (CNS) and initiate demyelinating pathology. We have used flow cytometry to directly analyse the migration to the CNS of MBP-reactive CD4+ T cells labelled with a lipophilic fluorescent dye (PKH2), in SJL/J mice with passively transferred EAE. Labelled cells constituted about 45% of the CNS CD4+ population at the time of EAE onset. Almost all (greater than 90%) of the PKH2-labelled CD4+ T cells from EAE CNS were blasts and were alpha/beta T cell receptor (TCR)+, CD44(Pgp-1)high, and the majority were CD45RB(low). By contrast, most PKH2-labelled CD4+ T cells in lymph nodes, although CD44high, were CD45RBhigh cells. The cells that were transferred to induce EAE were essentially similar to antigen-primed lymph node cell populations, containing less than 15% CD44high cells, and most of them were CD45RBhigh. The CD44high CD45RB(low) phenotype is characteristic of memory/effector T cells that have been activated by antigen recognition. The difference in CD45RB expression between CNS and LN could therefore reflect differential exposure and/or response to antigen. Consistent with this, PKH2-labelled CD4+ cells isolated from the CNS were responsive to MBP in vitro, whereas PKH2+ CD4+ cells from lymph nodes showed almost undetectable responses. In control experiments in which ovalbumin (OVA)-reactive T cells were transferred, a small number of fluorescent-labelled CD4+ T cells were also detected in CNS, but there were very few blasts, and these remained CD45RBhigh. These results argue for induction of the memory/effector phenotype of CD4+ T cells, and their selective retention in the CNS, as a consequence of antigen recognition.     

Growth hormone is a modulator of lymphocyte migration

Cell migration is crucial for intrathymic T cell differentiation and export of mature T lymphocytes to the peripheral lymphoid organs. The intrinsic regulation of T cell migration, mediated by adhesion molecules and chemokines, can be influenced by a number of endogenous factors, such as hormones, as for instance growth hormone (GH). Laminin deposition was enhanced in GH-treated mice and in GH-transgenic animals, compared with corresponding controls, and thymocyte adhesion to laminin was increased by in vivo GH treatment. An enhancing effect was also observed ex vivo in relation to the number of migrating cells in laminin-coated transwell chambers. Additionally, we found that the chemokine CXCL12, in conjunction with laminin, further enhanced the migration of thymocytes previously exposed to high concentrations of GH in vivo. Moreover, an increase in CXCL12 production has been detected in the thymus of GH-transgenic mice as well as in primary thymic epithelial cell cultures derived from these animals, as compared to age-matched wild-type counterparts. In keeping with these data, in vivo experiments showed that GH favors the trafficking of naive CD4+CD8- recent thymic emigrants to the peripheral lymph nodes. In addition, we found that migration of lymphocytes from mesenteric lymph nodes of GH-transgenic mice, triggered by the chemokine CXCL12, in conjunction with laminin or fibronectin, was enhanced, when compared to lymphocytes from control mice. Since GH-based therapy has been used in human and experimental infectious diseases, this hormone can be envisioned as an additional therapeutic tool in situations in which increasing lymphocyte numbers and migration are required for correcting a given pathological state.     

睾丸内胰岛移植对CD4+ CD25+调节性T细胞分布的影响

背景：CD4+ CD25+调节性T细胞是维持机体免疫耐受的重要调控者，参与了多种移植免疫耐受的诱导。 目的：拟观察小鼠睾丸内胰岛移植后CD4+ CD25+调节性T细胞分布的特点。 设计、时间及地点：观察对照动物实验，2007-04/2008-01在江西省实验动物中心完成。 材料：成年Balb/c小鼠。 方法：分离小鼠胰岛细胞，采用胰管内注射胶原酶水浴消化及Ficoll 400不连续密度梯度离心法纯化，以双硫腙染色，计算胰岛细胞纯度，以体外葡萄糖刺激胰岛素分泌试验判定胰岛细胞功能。将胰岛移植至小鼠睾丸或肾包膜下，每只移植300~400个胰岛。在胰岛移植24 h后麻醉处死小鼠，取脾脏、睾丸及淋巴结，制成细胞悬液，免疫磁珠法分离CD4+CD25+ T细胞，通过流式细胞仪分析计数。 主要观察指标：胰岛细胞的纯度及功能，CD4+ CD25+调节性T细胞的分布。 结果：纯化后每只胰腺获得(478±53)个胰岛细胞，纯度为(81.5±12.3)%，纯化后细胞形态完好，活度大于90%。睾丸内胰岛移植时，睾丸、淋巴结及脾脏中CD4+CD25+调节性T细胞均显著增多（P < 0.05~0.01）。 结论：睾丸内胰岛移植能明显上调睾丸、淋巴结及脾脏中CD4+ CD25+调节性T细胞数量。     

Differential responses of circulating prolactin, GH, and ACTH levels and distribution and activity of submaxillary lymph node lymphocytes to calorie restriction in male Lewis and Wistar rats

OBJECTIVES: Calorie restriction has been associated with anorexia in growing individuals, but the mechanisms involved are not known. Also, the effects of carbohydrates and lipid restriction in growing individuals were not studied. The aim of this study was to determine whether 66% calorie restriction (lipids and carbohydrates) differentially affects growing rats of the Wistar or Lewis strains. METHODS: Growing male Wistar and Lewis rats were subjected to 66% calorie restriction for 4 weeks. Plasma prolactin, growth hormone (GH), and adrenocorticotropic hormone (ACTH) levels were measured by specific radioimmunoassays. Likewise, lymphocytes from submaxillary lymph nodes were aseptically obtained to study absolute number of lymphocytes, cell surface markers (CD4+, CD8+, CD4+CD8+, B, and T cells), and proliferation. RESULTS: The body weight gain was lower in Lewis than in Wistar rats and was blunted in both strains by calorie restriction. Wistar and Lewis rats exhibited differential patterns of plasma prolactin, ACTH, and GH levels as well as proliferative capacities of T and B cells and their distribution in the submaxillary lymph nodes. Calorie restriction increased plasma prolactin and ACTH levels in Lewis as compared with Wistar rats. However, the plasma GH levels were diminished in both strains of rats by calorie restriction. All changes in plasma prolactin ACTH and GH levels seemed to correlate with the modifications observed in the distributions of T and B subsets in the submaxillary lymph nodes as well as in their proliferative capacity. CONCLUSIONS: Calorie restriction differentially modifies the secretory patterns of prolactin, GH, and ACTH in Lewis and in Wistar rats. These changes may explain, at least in part, the associated modifications in the proliferative capacity of submaxillary lymph node lymphocytes and in their distribution.     

Preferential increase of IL-2R+ CD4+ T cells and CD45RB- CD4+ T cells in the central nervous system in experimental allergic encephalomyelitis.

We examined lymphocytes isolated from the spinal cord (SC), peripheral blood (PB) and lymph nodes (LN) draining the immunization site of Lewis rats with acute experimental allergic encephalomyelitis (EAE). Cells were analysed for T cell subset markers CD4 (mAb W3/25) and CD8 (mAb OX8), for IL-2R (mAb OX39), and for high molecular mass leukocyte common antigen (LCA, CD45RB) expression (mAb OX22). T cells expressing high (CD45RB+) or low (CD45RB-) molecular mass LCA are of different maturational stages and/or separate lineages. CD4+ T cells were more predominant in SC than in PB and LN; CD8+ T cells were scarce in SC but common in PB and LN. Activated CD4+ T cells (IL-2R+) were common in the SC and LN but infrequent in blood. CD4+ T cells that were CD45RB+ were scarce in the SC. In contrast, the majority of CD4+ T cells in the PB and LN were CD45RB+. The preferential accumulation of IL-2R+ CD4+ T cells and of CD45RB- CD4+ T cells in the central nervous system (CNS) indicates that a selective mechanism directs cell egress into CNS lesions in EAE.     

Lymphocyte traffic changes induced by monolateral vagal denervation in mouse thymus and peripheral lymphoid organs

In this report we show that after monolateral vagal denervation (vagotomy), performed at the cervical level, a transient effect, lasting about 24 h, was produced on lymphocyte release from mouse thymus to peripheral lymphoid organs (spleen and lymph nodes). Labelling thymocytes in situ with fluorescein isothiocyanate (FITC) we note that the export of immature cells, CD4⁺CD8⁺, double positive (DP), and double negative, CD4⁻CD8⁻ (DN), from the thymus was consistently increased 24 and 48 h after vagotomy. Double staining with anti-L3T4 (CD4) and anti-mouse CD8α showed that the number of DP and UN cells was significantly higher in both spleen and lymph nodes of vagotomized mice compared to controls (sham-operated), whereas the percentage of CD4⁺CD8⁻ and CD8⁺CD4⁻, single positives (SP), was decreased. Considering thymic cellularity and apoptotic values, we exclude the non-specific effect of stress and suggest that this phenomenon could be in part due to a transient lack of the facilitating influence exerted by vagal efferent fibers on lymphocyte traffic at the cortico-medullary junction of the thymic gland, where mature cells, SP, leave the thymus to enter systemic circulation.     

Effect of chronic ethanol feeding on 24-hour rhythms of mitogenic responses and lymphocyte subset populations in thymus and spleen of peripubertal male rats

This work analyzes the effect of chronic ethanol feeding on the 24-hour variation of mitogenic responses and lymphocyte subset populations in thymus and spleen. Animals were maintained under a 12:12-hour light/dark photoperiod and they received a liquid diet for 4 weeks, starting on day 35 of life. The ethanol-fed group received a similar diet to controls except that maltose was isocalorically replaced by ethanol. Ethanol replacement provided 36% of the total caloric content of the diet. Rats were killed at 6 time intervals around the clock, beginning at Zeitgeber time (ZT) 1 (ZT 0 = lights on). Under ethanol intake the splenic and thymic weight decreased. In addition, mean values of the thymic, but not of the splenic T cell number decreased, and mean values of the thymic and splenic CD8+ and CD4+CD8+ number increased. Consequently, the thymic T/B ratio and the thymic and splenic CD4+/CD8+ ratio decreased in ethanol-fed rats. At the same time there was a significant increase in the response of the thymic cells to LPS. The ethanol diet modified the 24-hour rhythmicity of thymic and splenic T, B and CD4+CD8+ cells, thymic CD4+ and splenic CD8+ cells, thymic and splenic T/B and CD4+/CD8+ ratios, as well as of mitogenic responses in both tissues. Chronic ethanol administration presumably affects the endogenous clock that modulates the circadian variation of immune responsiveness in growing rats.     

Is there a role for cellular prion protein in intrathymic T cell differentiation and migration?

The cellular prion protein (PrP(C)) is expressed in the nervous and immune systems. Functionally, PrP(C) has been suggested to participate in neuron survival, neuritogenesis and T lymphocyte activation. Moreover, PrP(C) interaction with laminin influences neuronal adhesion and neurite extension. Nevertheless, so far the physiological role of PrP(C) has not been completely elucidated, particularly in the immune system. The aim of the study was to evaluate the possible participation of PrP(C) in intrathymic T cell development. We evaluated T cell differentiation markers in thymocytes and peripheral lymphocytes, as well as thymocyte death in PrP(C)-null or PrP(C)-overexpressing (Tga20) mice, compared to wild-type controls. In these same animals, we ascertained laminin-driven thymocyte migration. Compared to controls, only marginal differences were found in PrP(C)-null animals. However, Tga20 mice exhibited a severe thymic hypoplasia, with 10-20% lymphocytes compared to wild-type counterparts. In particular, the frequency of CD4+CD8+ cells was largely reduced, and this was accompanied by a dramatic increase in the frequency of CD4-CD8- thymocytes, which could be as high as 60-65% of the whole-cell suspensions. Moreover, Tga20 mice exhibited an increase in thymocyte death, comprising the CD4+CD8+, as well as CD4+ and CD8+ single-positive cells. Additionally, laminin-driven migration was largely impaired in Tga20 mice, in which we also found a significant decrease in total T lymphocytes in the spleen and lymph nodes. Our results show that PrP(C) overexpression alters intrathymic T cell development, a defect that likely has a negative impact in the formation of the T cell peripheral pool.     

Enhanced adherence of endothelial cells to blood mononuclear cells in HAM/TSP]

We investigated the adhesion of blood mononuclear cells (MNC) isolated from patients with HTLV-1-associated myelopathy (HAM/TSP). MNC from HAM/TSP patients were significantly more adherent to activated endothelial monolayers than MNC from non-HAM/TSP (controls and HTLV-1 carriers) subjects. Blocking studies demonstrated that the adhesion molecules VLA-4 (CD49d), ICAM-1 (CD54), and L-selectin (CD62L) all contributed to increased binding. However, anti-ICAM-1 antibody was the most efficient in inhibiting binding HAM/TSP patients MNC to activated endothelial cells. Expression on MNC of molecules involved in adhesion was also studied by flow cytometry in HAM/TSP patients, HTLV-1 carriers, and healthy control subjects after two days culture without any mitogen. In HAM/TSP patients, L-selectin expression on CD4+ and CD8+ subsets was lower than in controls; interestingly, HAM/TSP patients had lower percentage of CD4+ subset expressing L-selectin than HTLV-1 carriers. The percentage of CD4+ and CD8+ cells expressing VLA-4 was found to be similar to controls in both HAM/TSP patients and HTLV-1 carriers. Following two days in culture without mitogen, the percentage of T cells expressing ICAM-1 increased in HAM/TSP and carriers, but not in controls. This study provides information regarding trans-endothelial migration of MNC across the blood brain barrier in HAM/TSP and suggests ICAM-1 and its counterpart molecule LAF-1 are involved in massive infiltration of lymphocytes observed in the spinal cord.     

Increase in expression of adhesion molecule receptors on T helper cells during antipsychotic treatment and relationship to blood-brain barrier permeability in schizophrenia

OBJECTIVE: The authors estimated the expression of adhesion molecule receptors (VLA-4 and LFA-1) on T helper (CD4+) and T suppressor/cytotoxic (CD8+) lymphocytes in schizophrenic patients before and during antipsychotic treatment and studied the relationship of these subpopulations to CSF measures and blood-brain barrier permeability. METHOD: Blood was drawn from hospitalized patients with schizophrenia before (N = 45) and after (N = 22) neuroleptic treatment and from an age-matched comparison group (N = 41). Lumbar punctures were performed on 32 of the schizophrenic patients. RESULTS: During antipsychotic treatment there were significant increases in the percentage of VLA-4+/CD4+ and VLA-4+/CD8+ cells. VLA-4+/CD4+ and LFA-1+/CD4+ cells were both closely related to disturbance of the blood-brain barrier. Higher values for VLA-4+/CD4+ and LFA-1+/CD4+ cells were found in patients with a disturbed blood-brain barrier. CONCLUSIONS: The findings suggest that adhesion molecules are involved in immunoregulation between the central nervous system and the peripheral immune system in schizophrenia.     

Pharmacological hyperprolactinemia attenuates hydrocortisone-induced expression of CD11b on human CD8+ cells in vivo

OBJECTIVE: To study the short-term influences of pharmacologic hyperprolactinemia on hydrocortisone (HC)-induced effects on selected immune parameters. METHODS: A single dose of HC (40 mg per os) was administered to eleven healthy female volunteers 1 h after domperidone (10 mg per os) or placebo administration. Immune cell subsets and expression of adhesion molecules was assessed by flow cytometry at baseline and 4 and 6 h after HC administration. Intracellular staining of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) production in CD4+ lymphocytes after phorbol myristate acetate and ionomycin stimulation was performed at the same time points. RESULTS: HC administration was followed by a significant increase in cortisol levels, numbers of leukocytes and granulocytes and the percentage of CD16+, CD19+, CD11a+, CD11a+CD8+, CD11b+ and CD11b+CD8+ cells. The number of lymphocytes and monocytes and the percentage of CD3+, CD4+, CD4+/CD8+ ratio, CD62L+, CD54+ and CD54+CD16+ cells decreased, while the percentage of CD8+ cells was unaffected. Domperidone administration resulted in a significant increase in prolactin (PRL) concentrations. During hyperprolactinemia, the HC-induced increase in CD11b+CD8+ cells was significantly (p < 0.05) attenuated at 4 h. HC-induced changes in other immune parameters remained unaffected. No significant changes in the intracellular production of IL-4 and IFN-gamma in CD4+ lymphocytes were observed after a single dose of HC alone or during hyperprolactinemia. CONCLUSIONS: This study shows an attenuated HC-induced increase in CD11b+CD8+ cells in the peripheral blood of healthy females during hyperprolactinemia. Our in vivo observations suggest that short-term interactions occur between PRL and glucocorticoids, affecting selected immune functions. Further studies are needed for confirmation of these results.     

Differential effects of light/dark recombinant human prolactin administration on the submaxillary lymph nodes and spleen activity of adult male mice

OBJECTIVES: Day/night variations in cellularity, percentage of CD4+, CD8+ and double-positive (CD4+-CD8+) lymphocytes, lipopolysaccharide (LPS)- and concanavalin A (Con A)-induced lymphocyte proliferation and natural killer (NK) activity, and the effect of timed administration of recombinant human prolactin (h-PRL) on the above-mentioned parameters were investigated in the submaxillary lymph nodes and spleen of adult male mice. RESULTS: In controls, the percentage of CD4+, double-positive lymphocytes, LPS- or Con A-induced blastogenic proliferation and NK activity in the spleen differ during the dark phase as compared to the light phase. When administered during the dark period, h-PRL induced immunosuppresion in the percentage of CD4+, double-positive (CD4+-CD8+) lymphocytes. Con A- and LPS-induced lymphocyte proliferation and NK activity as compared to untreated controls. When h-PRL was administered during the light period, the cellularity increased, and h-PRL was immunosuppressive in Con A- and LPS-induced lymphcoyte proliferation and NK activity as compared to controls. Moreover, in control submaxillary lymph nodes the cellularity, percentage of CD8+, double-positive lymphocytes, blastogenic proliferation in the presence of Con A and LPS and NK activity differ when comparing the dark with the light phase. When administered during the dark period h-PRL induced immunosuppression in the percentage of double-positive (CD4+-CD8+) lymphocytes, Con A- and LPS-induced lymphocyte proliferation as compared to controls. When h-PRL is administered during the light period, no effects were observed. CONCLUSIONS: These results indicate the existence of differential day/night variations in the cellular immune response depending upon the lymphoid organ considered. Because of the administration of h-PRL a differential modulation of this circadian variation was also observed.     

Pituitary adenylate-cyclase-activating polypeptide expression in the immune system

Although pituitary adenylate-cyclase-activating polypeptide (PACAP) is a multifunctional and pleiotropic neuropeptide with many different immunomodulatory properties, investigations of its source in lymphoid organs are scarce. The present report contributes to the knowledge on the origin and synthesis of this peptide in immune cells of the lymphoid organs and peritoneum using immunohistochemistry, immunocytochemical staining, Western blot and RT-PCR methods. Our study reveals PACAP immunoreactivity in the thymus, spleen and lymph nodes. Cytochemical results show that PACAP is present in thymocytes, lymphocytes and plasma cells from the spleen and lymph nodes. Western blot analysis showed a band corresponding to PACAP for all lymphoid organs studied. mRNA appears in both double (CD4+CD8+)- and single-positive (CD4+CD8-, CD4-CD8+) thymocytes and in T subsets and B cells from the spleen and lymph nodes. In addition, PACAP mRNA is expressed in lymphocytes, but not in macrophages from peritoneal suspensions. Our findings show that PACAP produced by lymphocytes could be added to the growing list of mediators shared by nervous, endocrine and immune systems. Moreover, PACAP could be considered as a lymphocyte-derived cytokine in the central and peripheral lymphoid organs acting on lymphocytes and stromal cells.     

Time-dependent effect of cyclosporine on mitogenic responses and lymphocyte subset populations in rat spleen and submaxillary lymph nodes

Lipopolysaccharide (LPS)- and concanavalin A (ConA)-induced proliferation and T lymphocyte subsets were measured in spleen and submaxillary lymph nodes of male rats injected with cyclosporine (5 mg/kg s.c. for 5 days, at 12.00 or 24.00 h; animals kept under light from 08.00 to 20.00 h daily). One hour before the third injection, Freund's complete adjuvant or its vehicle was administered. A suppressive effect of cyclosporine on the mitogenic action of LPS was seen in the spleen of rats injected with cyclosporine at noon whereas the effect of ConA remained unaffected. CD4+, CD8+ and CD4+-CD8+ cells decreased in spleen and lymph nodes of Freund's adjuvant-injected rats only with cyclosporine given at noon. The results further support occurrence of time-of-day-dependent effects of cyclosporine on lymphocyte subsets and proliferation.     

CD8+ T cell activation correlates with disease activity in clinically isolated syndromes and is regulated by interferon-beta treatment

An increased percentage of blood CD8+ T cells from patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) was found to express CD26 and CD69. The percentage of CD26 or CD69 positive CD8+ T cells was higher in patients with MRI evidence of disease dissemination in space or with active MRI lesions than in the remaining patients. Treatment of MS with interferon (IFN)-beta resulted in a decrease in the percentage of CD26 and CD71 positive CD8+ T cells and an increase in the percentage of CD8+ T cells that expressed interleukin (IL)-10 and IL-13. CD8+ T cell activation in MS may be linked to disease activity already at disease onset, and is regulated by treatment with IFN-beta.     

Expression of CCR7 and CD45RA in CD4+ and CD8+ subsets in cerebrospinal fluid of 134 patients with inflammatory and non-inflammatory neurological diseases

We investigated CD45RA and CCR7 expression in CD4+ and CD8+ subsets of cerebrospinal fluid (CSF) lymphocytes, both immediately ex vivo and after stimulation, from 134 patients with a variety of inflammatory and non-inflammatory neurological diseases. Most inflammatory diseases had a higher CD4+:CD8+ ratio and higher percentage of effector memory T cells (T(EM)) than non-inflammatory controls, excluding active infection. Moreover, we found that patients with highly elevated cell counts in the CSF tended to have a lower percentage of central memory T cells (T(CM)) than patients with low or absent pleocytosis, with a concomitant increase in T(EM). We also found that samples with elevated IgG index or presence of oligoclonal bands had a significantly higher CD4+:CD8+ ratio than normal samples, consistent with increased CD4+ help for intrathecal IgG synthesis by B cells.     

Altered expression of Th1-type chemokine receptor CXCR3 on CD4+ T cells in myasthenia gravis patients

The expression of chemokine receptors on peripheral blood lymphocytes and thymocytes of myasthenia gravis (MG) patients was analyzed before and after therapy with special reference to the thymic histopathology. Before therapy, MG patients showed reduced frequency of CD4+ T cells expressing T-helper1 (Th1) type chemokine receptor CXCR3, with a significantly lower frequency in the thymoma group than in the thymic hyperplasia group, while the frequencies of CXCR3-positive CD8+ T cells remained normal irrespective of the thymic pathology. Both CD4+ cells and CD8+ cells of the hyperplasia group showed significantly increased expression of CCR1 on the cells followed by a reduction to the control level after therapy. No significant changes in the frequencies of CCR2, CCR3, CCR4, and CCR5 were observed in either MG group. There was a significant inverse correlation between the percentage of CXCR3-positive CD4+ T cells and the disease severity assessed with the MGFA scale (Fig. 1, r=-0.55, p=0.0047). The CXCR3 expression on CD4+ cells was increased toward the control level long after the initiation of therapy. The thymomas showed significantly higher percentages of CXCR3-positive CD4+CD8- single positive cells than the control thymuses and, though not significantly, the hyperplastic thymuses also showed higher percentages. These results indicated that Th1-type chemokine signalings were altered in the MG patients, particularly those with thymoma, and that the thymus and thymoma are important sites of Th1-type reactions. The slow clinical improvement of MG symptoms after treatment may be explained partly by the gradual normalization of CXCR3-mediated signaling.     

Effects of growth hormone on thymocyte development from progenitor cells in the bone marrow.

The effect of growth hormone (GH) on T cell differentiation was studied in young and old mice, employing in vivo and in vitro experimental approaches. Injections of GH during a period of 3 months to young and old mice resulted in a significant increase in the cell number and the percentage of CD3+ cells in the thymus of the old, but not in the young mice. Treatment of intact fetal thymus (FT) lobes with recombinant human GH (hGH) had no significant effect on cell numbers or on the values of CD4/CD8 thymocyte subsets. When partially depleted FT (10 Gy) were colonized with bone marrow (BM) cells and subsequently cultivated on monolayers of GH3, a GH-secreting cell line, the values of T cells deriving from the donor BM cells were elevated. Treatment with hGH to cocultures of lymphoid-depleted FT (dGUA) with BM lent further support to the idea that GH affects the newly emigrating BM cells, rather than the resident thymocytes. The results suggest that GH affects the thymocyte progenitors in the BM at the early stage of their development in the thymus.     

Increase in peripheral CD4 bright+ CD8 dull+ T cells in Parkinson disease

BACKGROUND: Immune abnormalities are known to be involved in the pathogenesis of sporadic Parkinson disease. OBJECTIVE: To examine whether abnormalities in peripheral lymphocytes exist in Parkinson disease. METHODS: Immune mediators, including CD1a, CD3, CD4, CD8, CD45RO, and Fas (CD95), were examined in peripheral lymphocytes of patients by 3-color flow cytometry. RESULTS: Patients with Parkinson disease displayed a significantly greater population of circulating CD3+ CD4 bright+ CD8 dull+ lymphocytes than age-matched control subjects (P =.005) and patients with cerebrovascular disease (P =.002). The increase in these cells appeared to continue for at least 17 months. These T cells also expressed CD45RO and Fas, markers for activated T cells, while CD1a, a marker for thymic T cells, was negative, suggesting that these cells are mature T cells with immune activities. CONCLUSIONS: As CD4+ CD8+ T cells are known to increase after some specific viral infections, the continuous increase in CD4 bright+ CD8 dull+ T cells shown here may indicate postinfectious immune abnormalities that are possibly associated with the pathogenesis of this slowly progressive, multifactorial neurodegenerative disease.     

Neonatal testosterone imprinting affects thymus development and leads to phenotypic rejuvenation and masculinization of the peripheral blood T-cell compartment in adult female rats

Exposure of female rodents to testosterone in the critical neonatal period produces defeminization/masculinization of the hypothalamo–pituitary–gonadal (HPG) axis, i.e. neonatal androgenization and postpones axis maturation. To address the hypothesis that HPG axis signaling is involved in the programming of thymic maturation/involution and sexual differentiation we studied the impact of neonatal androgenization on thymic cellularity, development of effector and regulatory T cells, and phenotypic characteristics of peripheral blood T lymphocytes in adult rats. A single injection of testosterone on postnatal day 2 postponed thymic maturation/involution as revealed by organ hypercellularity, increased cellularity of the most mature (CD4+CD8? and CD4?CD8+) TCRαβ^high thymocyte and both recent thymic emigrant (RTE) subsets and caused phenotypic defeminization/masculinization of thymic (decreased CD4+CD8?TCRαβ^high/CD4?CD8+TCRαβ^high cell ratio) and peripheral blood T-cell compartments (decreased CD4+RTE/CD8+RTE and CD4+/CD8+ cell ratio). In addition, neonatal androgenization increased the relative and absolute numbers of both CD4+CD25+Foxp3+ and natural killer (NK) regulatory T cells in peripheral blood. These findings, in conjunction with thymocyte overexpression of Thy-1 that is assumed to reduce negative selection affecting self-reactive cell generation, suggest a new relationship between self-reactive and regulatory T cells. In conclusion, our study provides additional evidence for a role of HPG signals (i.e. sex steroids and gonadotropins) in programming the kinetics of thymic maturation/involution and in establishing immunological sexual dimorphism.