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Peripheral T Cells (peripheral t + cell)
Selected AbstractsLow-dose cyclosporine A therapy increases the regulatory T cell population in patients with atopic dermatitisALLERGY, Issue 11 2009C. Brandt Background:, Atopic dermatitis (AD) is a T cell dependent chronic relapsing inflammatory skin disorder successfully treated with cyclosporine A (CsA). Clinical observations indicate that even low-dose CsA therapy is successful in severely affected AD patients. We studied the impact of low-dose CsA therapy on the ability of T helper cells to be activated, and examined whether regulatory T (Treg) cells are increased in these patients. Methods:, Peripheral T cells were activated in a whole blood sample and interleukin-2 producing cells were measured by intracellular cytokine staining. Regulatory T cells were analyzed by intracellular FoxP3 staining. Regulatory T cells (CD4+CD25+CD127low) and effector T cells (CD4+CD25,CD127+) were sorted by flow cytometry and used for suppression assays. Results:, A group of AD patients treated with low-dose CsA had a significantly larger Treg cell population than a healthy control subject group. In individual patients, onset of low-dose CsA therapy reduced the ability of T cells to be activated to 42 ± 18% (P < 0.005) and significantly increased Treg cells, both in absolute numbers (1.6-fold change) and frequencies (1.7-fold change). Treg cells from AD patients showed similar suppressive capacities as Treg cells from healthy donors. Furthermore, Treg cells from AD patients had skin homing properties. Conclusion:, Our results indicate that the therapeutic effect of low-dose CsA therapy in AD patients might be not only mediated by the inhibition of T cell hyperactivity but also by an increased population of Treg cells. [source] LKB1 is essential for the proliferation of T-cell progenitors and mature peripheral T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2010Peter Tamás Abstract The serine/threonine kinase LKB1 has a conserved role in Drosophila and nematodes to co-ordinate cell metabolism. During T lymphocyte development in the thymus, progenitors need to synchronize increased metabolism with the onset of proliferation and differentiation to ensure that they can meet the energy requirements for development. The present study explores the role of LKB1 in this process and shows that loss of LKB1 prevents thymocyte differentiation and the production of peripheral T lymphocytes. We find that LKB1 is required for several key metabolic processes in T-cell progenitors. For example, LKB1 controls expression of CD98, a key subunit of the L -system aa transporter and is also required for the pre-TCR to induce and sustain the regulated phosphorylation of the ribosomal S6 subunit, a key regulator of protein synthesis. In the absence of LKB1 TCR-,-selected thymocytes failed to proliferate and did not survive. LBK1 was also required for survival and proliferation of peripheral T cells. These data thus reveal a conserved and essential role for LKB1 in the proliferative responses of both thymocytes and mature T cells. [source] MSK regulate TCR-induced CREB phosphorylation but not immediate early gene transcriptionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2007Madlen Kaiser Abstract Stimulation of the T cell receptor activates the ERK1/2 and p38 mitogen-activated protein kinase (MAPK) cascades. We demonstrate that TCR stimulation also activates the mitogen- and stress-activated kinases (MSK) downstream of ERK1/2 and p38 in both a T cell line and primary peripheral T cells. MSK1/2-knockout mice were found to have normal numbers of T cells in the thymus, and development of these cells appeared unaffected. Using naive T cells and T lymphoblasts from MSK1/2-knockout mice, it was found that MSK was the kinase responsible for phosphorylation of the transcription factor CREB in response to TCR stimulation. Phosphorylation of CREB by MSK has been linked to the transcription of nur77, nor1 and c-fos downstream of MAPK signalling in various cell types. In T cells, the TCR-dependent transcription of these genes was found to require a MAPK-dependent but MSK-independent signalling pathway. Nevertheless, the number of T cells present in the spleens of MSK1/2-knockout mice and the IL-2-induced proliferation of these cells was reduced compared to wild-type mice. This correlated to a reduction in the TCR-induced up-regulation of the IL-2 receptor CD25 and a requirement for MSK in IL-2-induced CREB phosphorylation. [source] IL-7 inhibits dexamethasone-induced apoptosis via Akt/PKB in mature, peripheral T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2003Hadassah Sade Abstract We have investigated the mechanism of IL-7-mediated inhibition of dexamethasone-induced apoptosis in T cells. Broad-spectrum caspase inhibitors block dexamethasone-triggered nuclear fragmentation, but not the loss of mitochondrial transmembrane potential or membrane integrity in CD3+ mature T cells isolated from adult mouse spleens. IL-7 blocked dexamethasone-induced apoptosis and the processing of caspase-3 and caspase-7. IL-7 also blocked dexamethasone-triggered dephosphorylation of the serine-threonine kinase Akt/PKB and its target, the Ser136 residue in Bad. The loss of anti-apoptotic proteins Bcl-xL and inhibitor of apoptosis protein-2 (IAP-2) was also blocked by IL-7. The protective effect was attenuated by pharmacological inhibitors of phosphatidylinositol-3 kinase (PI3K) with one exception: inhibition of PI3K did not abrogate Bcl-xL expression in the presence of IL-7. The anti-apoptotic role of Akt suggested by these experiments was tested by overexpression of constitutively active Akt, which blocked dexamethasone-induced apoptosis and elevated IAP-2 but not Bcl-xL levels in a mature T cell line. Thus, IL-7 regulates IAP-2 expression and inhibits dexamethasone-induced apoptosis by activating Akt via PI3K-dependent signaling, but regulates Bcl-xL expression via a PI3K-independent pathway in mature T cells. [source] T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and toleranceIMMUNOLOGICAL REVIEWS, Issue 1 2009Robert J. Salmond Summary:, T-cell development in the thymus and activation of mature T cells in secondary lymphoid organs requires the ability of cells to respond appropriately to environmental signals at multiple stages of their development. The process of thymocyte selection insures a functional T-cell repertoire, while activation of naive peripheral T cells induces proliferation, gain of effector function, and, ultimately, long-lived T-cell memory. The T-cell immune response is initiated upon engagement of the T-cell receptor (TCR) and coreceptor, CD4 or CD8, by cognate antigen/major histocompatibility complexes presented by antigen-presenting cells. TCR/coreceptor engagement induces the activation of biochemical signaling pathways that, in combination with signals from costimulator molecules and cytokine receptors, direct the outcome of the response. Activation of the src- family kinases p56lck (Lck) and p59fyn (Fyn) is central to the initiation of TCR signaling pathways. This review focuses on our current understanding of the mechanisms by which these two proteins orchestrate T-cell function. [source] Regulatory T cells and autoimmune diseaseIMMUNOLOGICAL REVIEWS, Issue 1 2005Silke Paust Summary:, Although T-cell clones bearing T-cell receptors with high affinity for self-peptide major histocompatibility complex (MHC) products are generally eliminated in the thymus (recessive tolerance), the peripheral T-cell repertoire remains strongly biased toward self-peptide MHC complexes and includes autoreactive T cells. A search for peripheral T cells that might exert dominant inhibitory effects on autoreactivity has implicated a subpopulation of CD4+CD25+ T cells called regulatory T cells (Tregs). Here, we discuss the role of cytokines and costimulatory molecules in the generation, maintenance, and function of Tregs. We also summarize evidence for the involvement of Tregs in controlling autoimmune diseases, including type 1 diabetes, experimental autoimmune encephalomyelitis, and inflammatory bowel disease. Last, we discuss our recent definition of the potential role of B7 expressed on activated T-effector cells as a target molecule for Treg-dependent suppression. These observations suggest that the engagement of B7 on effector T cells transmits an inhibitory signal that blocks or attenuates effector T-cell function. We restrict our comments to the suppression mediated by cells within the CD4 lineage; the impact of the cells within the CD8 lineage that may suppress via engagement of Qa-1 on effector T cells is not addressed in this review. [source] Defective T-cell function leading to reduced antibody production in a kleisin-, mutant mouseIMMUNOLOGY, Issue 2 2008Katharine M. Gosling Summary The recently described nessy (Ncaph2nes/nes) mutant mouse strain has a defect in T-cell development caused by a mutation in the ubiquitous kleisin-, (also known as Ncaph2). Kleisin- , is a subunit of the condensin II complex involved in chromosome condensation during mitosis. The nessy phenotype is characterized by CD44hi CD8+ peripheral T cells, 10,20% of normal thymocyte numbers and 2·5-fold fewer ,, T cells in the spleen compared with wild-type mice. In this study we examined the effect of the nessy mutation in kleisin-, on the immune response by challenging mice with an attenuated strain of Salmonella. Results showed that nessy mice control bacterial load as effectively as wild-type mice but exhibit a reduced antibody titre. Further experiments revealed that while the T-dependent antibody response was diminished in nessy mice the T-independent response was normal, suggesting that the defect was the result of T-cell function and not B-cell function. In vitro activation assays showed that nessy T cells have a lower capacity to up-regulate the early activation marker CD69 than wild-type T cells. Upon transfer into RAG,/, mice, nessy and wild-type CD4 T cells showed equivalent homeostatic proliferation, while nessy CD8 T cells proliferated more than their wild-type counterparts. When cultured with anti-T-cell receptor , or concanavalin A, nessy T cells were found to die faster than wild-type T cells. These data indicate that kleisin-, is required for a normal immune response, and represent the first demonstration of a role for kleisin-, in T-cell function. [source] Phenotypic analysis of peripheral CD4+ CD8+ T cells in the ratIMMUNOLOGY, Issue 2 2000E. Kenny Summary Among peripheral T cells, the expression of CD4 and CD8 is almost mutually exclusive. However, here we show, using flow cytometric analysis, that ex vivo approximately 6% of rat T cells stained for both CD4 and CD8. These double positive cells were also detected by confocal microscopy. Only around 50% of double positive cells expressed the CD8, chain, the remaining cells expressed the CD8, chain alone. Double positive cells were blast-like with a phenotype, distinct from that of either CD4 or CD8 single positive cells, suggestive of an activated state. Previous reports of double positive T cells have also suggested that coexpression of CD4 and CD8 is linked to the activation state of the cell. There was an indication that priming animals with a hapten-carrier complex increased the ratio of CD8,,,:,,, expressing double positive T cells, although we did not detect an increase in the frequency of double positive T cells following priming. We also show that the frequency of double positive cells was reduced following thymectomy and with age. In conclusion, these studies show that peripheral T cells expressing both CD4 and CD8 can be detected in the rat and that they are phenotypically distinct from CD4 and CD8 single positive T cells. [source] Phenotypical and functional analysis of T cells in periodontitisJOURNAL OF PERIODONTAL RESEARCH, Issue 4 2001M. D. A. Petit To explore aspects of cellular immune responses in the pathogenesis of periodontitis we analyzed phenotype and function of peripheral T cells. Two groups of subjects participated: one group consisted of 10 highly susceptible patients with severe periodontitis (mean age 29 years) and a control group consisted of 10 age, gender and race matched subjects with gingivitis. From all subjects peripheral blood was collected. The results showed that the numbers of CD3+, CD4+ and CD8+ T cells as well as the CD4/CD8 ratio, and the proliferative capacity of T cells, were not different between the two groups of subjects. Also, proportions of naive and memory T cells for both the CD4+ and CD8+ subpopulations were not different. Functional heterogeneity within the CD4+ and CD8+ T cell compartments was determined by intracellular analysis of interferon- ,(IFN- ,) and interleukin-4 (IL-4) production. On the basis of these latter analyses among CD4+ and CD8+ cells, T helper (Th) 1 or Th2 function and T cytotoxic (Tc) 1 or Tc2 function, respectively, could be deduced. No significant differences in proportions of CD4+ and CD8+ T cells positive for intracellular IFN- , or IL-4 were observed between periodontitis patients and gingivitis controls; however a higher level of intracellular IL-4 in CD8+ T cells was seen in periodontitis patients. This might indicate that there is a shift towards a Tc2 function within the CD8+ T cell subpopulation. The current explorative study suggests that further research into the role of CD8+T cells in the pathogenesis of periodontitis is warranted. [source] Glutamate levels and activity of the T cell voltage-gated potassium Kv1.3 channel in patients with systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 5 2008C. Poulopoulou Objective Alterations in glutamate homeostasis and Kv1.3 voltage-gated potassium channel function have been independently associated with T cell dysfunction, whereas selective blockade of Kv1.3 channels inhibits T cell activation and improves T cell,mediated manifestations in animal models of autoimmunity. Because low extracellular glutamate concentrations enhance the activity of this channel in normal T cells ex vivo, we undertook this study to examine serum glutamate concentrations and Kv1.3 channel activity in patients with systemic lupus erythematosus (SLE). Methods We used high-performance liquid chromatography for glutamate measurements, and we used the whole-cell patch-clamp technique for electrophysiologic studies performed in freshly isolated, noncultured peripheral T cells. Results Mean ± SD serum concentrations of glutamate were lower in patients with either clinically quiescent SLE (77 ± 27 ,M [n = 18]) or active SLE (61 ± 36 ,M [n = 16]) than in healthy controls (166 ± 64 ,M [n = 24]) (both P < 0.0001). The intrinsic gating properties of the Kv1.3 channels in lupus T cells were found to be comparable with those in healthy control,derived T cells. Notably, electrophysiologic data from SLE patient,derived T cells exposed to extracellular glutamate concentrations similar to their respective serum levels (50 ,M) demonstrated Kv1.3 current responses enhanced by almost 20% (P < 0.01) compared with those subsequently obtained from the same cell in the presence of glutamate concentrations within control serum levels (200 ,M). Conclusion Based on the key role of Kv1.3 channel activity in lymphocyte physiology, an enhancing in vivo effect of low serum glutamate concentrations on the functional activity of this channel may contribute to lupus T cell hyperactivity. Studies to further elucidate Kv1.3 responses in SLE, as well as the possible pathogenetic role of this unsuspected metabolic abnormality, may have therapeutic implications for SLE patients. [source] Female mice are more susceptible to developing inflammatory disorders due to impaired transforming growth factor , signaling in salivary glandsARTHRITIS & RHEUMATISM, Issue 6 2007Seshagiri R. Nandula Objective Transforming growth factor , (TGF,) plays a key role in the onset and resolution of autoimmune diseases and chronic inflammation. The aim of this study was to delineate the precise function of TGF, signaling in salivary gland inflammation. Methods We impaired TGF, signaling in mouse salivary glands by conditionally inactivating expression of TGF, receptor type I (TGF,RI), either by using mouse mammary tumor virus,Cre mice or by delivering adenoviral vector containing Cre to mouse salivary glands via retrograde infusion of the cannulated main excretory ducts of submandibular glands. Results TGF,RI,conditional knockout (TGF,RI-coko) mice were born normal; however, female TGF,RI-coko mice developed severe multifocal inflammation in salivary and mammary glands and in the heart. The inflammatory disorder affected normal growth and resulted in the death of the mice at ages 4,5 weeks. Interestingly, male TGF,RI-coko mice did not exhibit any signs of inflammation. The female TGF,RI-coko mice also showed an increase in Th1 proinflammatory cytokines in salivary glands and exhibited an up-regulation of peripheral T cells. In addition, these mice showed an atypical distribution of aquaporin 5 in their salivary glands, suggesting likely secretory impairment. Administration of an adenoviral vector encoding Cre recombinase into the salivary glands resulted in inflammatory foci only in the glands of female TGF,RI,loxP-flanked (floxed) mice (TGF,RI-f/f mice), but not in those of male and female wild-type mice or male TGF,RI-f/f mice. Conclusion These results suggest that female mice are uniquely more susceptible to developing inflammatory disorders due to impaired TGF, signaling in their salivary glands. [source] Increased frequency of intracellular interleukin (IL)-13 and IL-10, but not IL-4, expressing CD4+ and CD8+ peripheral T cells of patients with atopic dermatitisBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2002M. Aleksza Summary Background A number of studies exist demonstrating the increased expression of type 2 cytokines and decreased capacity to produce interferon-, (IFN-,) in peripheral blood mononuclear cells (PBMCs) of patients with atopic dermatitis (AD). Objectives To clarify the results of recent studies concerning the role of interleukin (IL)-4 and IL-13 in PBMCs of AD patients, we analysed the activation status of lymphocyte subpopulations. Methods We measured the intracellular expression and serum levels of certain type 1 and type 2 cytokines, using cell surface and intracellular cytokine staining, flow cytometry and enzyme-linked immunosorbent assay techniques. Results The frequency of IL-10 and IL-13 producing CD4+ and CD8+ T cells was significantly higher in patients with AD, while the frequency of IFN-, secreting helper and cytotoxic T cells was significantly lower in patients with AD than in control subjects. The serum levels of IL-10 and IL-13 were also significantly increased. There were no significant differences observed between the experimental groups in the frequency of IL-4 producing CD4+ and CD8+ cells. Conclusions This study demonstrates a type 2 cytokine production in the CD4+ and CD8+ T cells of AD patients, which is characterized by an elevated IL-13, but not by IL-4 secretion, and by an increased level of the immunoregulatory IL-10, which can contribute to a decrease in IFN-, expression. [source] Transgenic mice expressing the T cell antigen receptor specific for an immunodominant epitope of a major allergen of house dust mite develop an asthmatic phenotype on exposure of the airways to allergenCLINICAL & EXPERIMENTAL ALLERGY, Issue 7 2005E. R. Jarman Summary Background Current studies on mechanisms underlying allergen-induced pulmonary inflammation and asthma are hampered by the lack of appropriate physiological in vivo models that reflect the natural route of allergen exposure and sensitization. Objective To generate and phenotype a transgenic mouse strain expressing the T cell receptor (TCR) specific for an immunodominant domain of the major inhalant allergen Dermatophagoides pteronyssinus species of house dust mite (Der p 1), for the development of an in vivo model of allergic asthma. Methods Der p 1 transgenic mice were generated using TCR-,, derived from a CD4+ T cell hybridoma reactive with Der p 1 residues p 110,131. The frequency and functional activity of peripheral T cells were determined and parameters of airway inflammation assessed following allergen challenge of the airways with Der p 1. Results CD4+ T cells are functionally active, exhibiting dose-dependent proliferation and IL-4 production on primary stimulation with Der p 1 or Der p 1, p 110,131 in vitro, independent of in vivo antigen priming. On sensitization of the airways with allergen, in the absence of systemic priming or the application of adjuvants, the TCR transgenic mice develop airway inflammation characterized by a marked lymphocytic and eosinophilic infiltrate with goblet cell hyperplasia and enhanced mucin production. Conclusion The Der p 1 TCR transgenic mice provide a model for investigating the pathophysiological mechanisms of pulmonary inflammation following sensitization by exposure of the airways to allergen and for investigating the mode of action and efficacy of novel immunotherapeutics. [source] | ||||||||||||||||||||||