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CD4+ T Cells (cd4+ t + cell)
Kinds of CD4+ T Cells Terms modified by CD4+ T Cells Selected AbstractsORIGINAL ARTICLE: Effects of Peritoneal Fluid from Endometriosis Patients on Interferon-,-Induced Protein-10 (CXCL10) and Interleukin-8 (CXCL8) Released by Neutrophils and CD4+ T CellsAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2009Ji-Yeon Kim Problem, Intraperitoneal immuno-inflammatory changes may be associated with the pathogenesis of endometriosis. We evaluated the effects of peritoneal fluid obtained from patients with endometriosis (ePF) on the release of interferon-,-induced protein-10 (IP-10/CXCL10) and interleukin-8 (IL-8/CXCL8) by neutrophils, CD4+ T cells, and monocytes. Method of study, Neutrophils, CD4+ T cells, and monocytes were cultured with ePF and the chemokine levels in the supernatants were then measured using enzyme-linked immunosorbent assay. Results, The addition of ePF to cultures of CD4+ T cells led to a significant increase in the release of IP-10 when compared with control PF without endometriosis (cPF). There was a positive correlation between the levels of IL-8 and IP-10 in ePF (R = 0.89, P = 0.041), but not between the levels of IP-10 and IL-8 released by neutrophils, CD4+ T cells, and monocytes. The levels of IP-10 in ePF were positively correlated with the release of IP-10 by ePF-treated neutrophils (R = 0.89, P < 0.001), CD4+ T cells (R = 0.93, P < 0.001), and monocytes (R = 0.70, P = 0.01). Moreover, the addition of ePF significantly enhanced the interferon-,-induced release of IP-10 by nuetrophils and CD4+ T cells. Conclusion, These findings suggest that neutrophils and T cells release differential levels of IP-10 and IL-8 in response to stimulation with ePF, and that these cells are a major source of IP-10 in the PF of endometriosis patients. [source] Isolated CD39 Expression on CD4+ T Cells Denotes both Regulatory and Memory PopulationsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009Q. Zhou Foxp3+ regulatory T cells (Tregs) express both ectoenzymes CD39 and CD73, which in tandem hydrolyze pericellular ATP into adenosine, an immunoinhibitory molecule that contributes to Treg suppressive function. Using Foxp3GFP knockin mice, we noted that the mouse CD4+CD39+ T-cell pool contains two roughly equal size Foxp3+ and Foxp3, populations. While Foxp3+CD39+ cells are CD73bright and are the bone fide Tregs, Foxp3,CD39+ cells do not have suppressive activity and are CD44+CD62L,CD25,CD73dim/,, exhibiting memory cell phenotype. Functionally, CD39 expression on memory and Treg cells confers protection against ATP-induced apoptosis. Compared with Foxp3,CD39, naïve T cells, Foxp3,CD39+ cells freshly isolated from non-immunized mice express at rest significantly higher levels of mRNA for T-helper lineage-specific cytokines IFN-, (Th1), IL-4/IL-10 (Th2), IL-17A/F (Th17), as well as pro-inflammatory cytokines, and rapidly secrete these cytokines upon stimulation. Moreover, the presence of Foxp3,CD39+ cells inhibits TGF-, induction of Foxp3 in Foxp3,CD39, cells. Furthermore, when transferred in vivo, Foxp3,CD39+ cells rejected MHC-mismatched skin allografts in a much faster tempo than Foxp3,CD39, cells. Thus, besides Tregs, CD39 is also expressed on pre-existing memory T cells of Th1-, Th2- and Th17-types with heightened alloreactivity. [source] Natural Antigenic Peptides from Squamous Cell Carcinoma Recognized by Autologous HLA-DR8,restricted CD4+ T CellsCANCER SCIENCE, Issue 8 2002Hiroaki Kondo A large number of human tumor antigens recognized by CD8+ cytotoxic T lymphocytes (CTL) have been identified. Some of them have been employed in clinical trials and have achieved some objective responses. However, little is known about those that are recognized by CD4+ T cells, except for a very few that were identified from melanomas. Previously, we reported that an oral squamous cell carcinoma (SCC) cell line, OSC,20, was effectively lysed by HLA-DRB1·08032 (HLA-DRS)-restricted autologous CD4+ T cell line, TcOSC,20. In this study, we performed two steps of chromatographic purification of the tumor cell lysate in combination with mass spectrometry. We found one reverse-phase high-performance liquid chromatography (RP-HPLC) fraction that was effectively recognized by the T cells. We analyzed the fraction by nano-liquid chromatography/electrospray ionization ion trap mass spectrometry (LC/MS/MS) and found six representative ions. We could determine the primary amino acid sequence of each of the six ions. Three of them contained a potential HLA-DR8 binding motif, and TcOSC,20 showed a rather strong cytotoxic response to one of the synthetic pep tides, namely, amino acid residues 321,336 of human a-enolase. Thus, several gene products of squamous cancer cells are endogenously processed and may be presented on HLA class II molecules, so that they could constitute target molecules for autologous CD4+ T cells. [source] CD4+ T cell help improves CD8+ T cell memory by retained CD27 expressionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2008Matthias Abstract CD4+ T cell help during the priming of CD8+ T lymphocytes imprints the capacity for optimal secondary expansion upon re-encounter with antigen. Helped memory CD8+ T cells rapidly expand in response to a secondary antigen exposure, even in the absence of T cell help and, are most efficient in protection against a re-infection. In contrast, helpless memory CTL can mediate effector function, but secondary expansion is reduced. How CD4+ T cells instruct CD8+ memory T cells during priming to undergo efficient secondary expansion has not been resolved in detail. Here, we show that memory CTL after infection with lymphocytic choriomeningitis virus are CD27high whereas memory CTL primed in the absence of CD4+ T cell have a reduced expression of CD27. Helpless memory CTL produced low amounts of IL-2 and did not efficiently expand after restimulation with peptide in vitro. Blocking experiments with monoclonal antibodies and the use of CD27,/, memory CTL revealed that CD27 ligation during restimulation increased autocrine IL-2 production and secondary expansion. Therefore, regulating CD27 expression on memory CTL is a novel mechanism how CD4+ T cells control CTL memory. [source] Patients with Epstein Barr virus-positive lymphomas have decreased CD4+ T-cell responses to the viral nuclear antigen 1INTERNATIONAL JOURNAL OF CANCER, Issue 12 2008Kevin N. Heller Abstract Epstein Barr virus (EBV) causes lymphomas in immune competent and, at increased frequencies, in immune compromised patients. In the presence of an intact immune system, EBV-associated lymphomas express in most cases only 3 or fewer EBV antigens at the protein level, always including the nuclear antigen 1 of EBV (EBNA1). EBNA1 is a prominent target for EBV-specific CD4+ T cell and humoral immune responses in healthy EBV carriers. Here we demonstrate that patients with EBV-associated lymphomas, primarily Hodgkin's lymphoma, lack detectable EBNA1-specific CD4+ T-cell responses and have slightly altered EBNA1-specific antibody titers at diagnosis. In contrast, the majority of EBV-negative lymphoma patients had detectable IFN, expression and proliferation by CD4+ T cells in response to EBNA1, and carry EBNA1-specific immunoglobulins at levels similar to healthy virus carriers. Other EBV antigens, which were not present in the tumors, were recognized in less EBV positive, than negative lymphoma patients, but detectable responses reached similar CD8+ T cell frequencies in both cohorts. Patients with EBV-positive and -negative lymphomas did not differ in T-cell responses in influenza-specific CD4+ T cell proliferation and in antibody titers against tetanus toxoid. These data suggest a selective loss of EBNA1-specific immune control in EBV-associated lymphoma patients, which should be targeted for immunotherapy of these malignancies. © 2008 Wiley-Liss, Inc. [source] Natural Antigenic Peptides from Squamous Cell Carcinoma Recognized by Autologous HLA-DR8,restricted CD4+ T CellsCANCER SCIENCE, Issue 8 2002Hiroaki Kondo A large number of human tumor antigens recognized by CD8+ cytotoxic T lymphocytes (CTL) have been identified. Some of them have been employed in clinical trials and have achieved some objective responses. However, little is known about those that are recognized by CD4+ T cells, except for a very few that were identified from melanomas. Previously, we reported that an oral squamous cell carcinoma (SCC) cell line, OSC,20, was effectively lysed by HLA-DRB1·08032 (HLA-DRS)-restricted autologous CD4+ T cell line, TcOSC,20. In this study, we performed two steps of chromatographic purification of the tumor cell lysate in combination with mass spectrometry. We found one reverse-phase high-performance liquid chromatography (RP-HPLC) fraction that was effectively recognized by the T cells. We analyzed the fraction by nano-liquid chromatography/electrospray ionization ion trap mass spectrometry (LC/MS/MS) and found six representative ions. We could determine the primary amino acid sequence of each of the six ions. Three of them contained a potential HLA-DR8 binding motif, and TcOSC,20 showed a rather strong cytotoxic response to one of the synthetic pep tides, namely, amino acid residues 321,336 of human a-enolase. Thus, several gene products of squamous cancer cells are endogenously processed and may be presented on HLA class II molecules, so that they could constitute target molecules for autologous CD4+ T cells. [source] Pneumonia in HIV-infected patients in the HAART era: Incidence, risk, and impact of the pneumococcal vaccinationJOURNAL OF MEDICAL VIROLOGY, Issue 4 2004C. López-Palomo Abstract The objective of this study was to assess the factors implicated in an increased or decreased risk of pneumonia, with particular attention to the response to highly active antiretroviral therapy (HAART) and the effect of the polysaccharide 23-valent pneumococcal vaccination in 300 human immunodeficiency virus (HIV)-infected adults followed-up for a median of 35.6 months. Pneumococcal pneumonia occurred in 12 patients and all bacterial pneumonia (pneumonia caused by Streptococcus pneumoniae or other bacteria, as well as those with negative cultures but presumably bacterial in origin) in 40 patients. In the univariate analysis, immunodepressed patients (defined as those with less than 200 CD4+ T cell/,l), those without immunological response to HAART (defined as an increase of 25% of CD4+ T lymphocyte count), patients with previous admissions to hospital and those with cotrimoxazole or Mycobacterium avium intracellulare prophylaxis showed a higher incidence of both pneumococcal and all bacterial pneumonia. Multivariate analysis demonstrated that the presence of pneumococcal pneumonia was associated with a CD4+ lymphocyte count at the time of HIV diagnosis <200 cells/,l. The multivariate model that was more valid for prediction of all bacterial pneumonia included a CD4+ T cell count <200 cells/,l and absence of immunological response to HAART. Only in patients with a baseline CD4+ T cell count lower than 200/,l and immunological response to HAART, a near significant lower incidence of all bacterial pneumonia was observed after vaccination. Thus, these results do not support an important additional protective effect of 23-valent pneumococcal vaccine in HIV-patients with immunological response to HAART. J. Med. Virol. 72:517,524, 2004. © 2004 Wiley-Liss, Inc. [source] Utility of CD26 in flow cytometric immunophenotyping of T-cell lymphomas in tissue and body fluid specimens,CYTOMETRY, Issue 6 2008Diane M. Pierson Abstract Background CD26 is expressed by most CD4+ T cells in normal peripheral blood specimens. Neoplastic T cells are frequently CD26, in mycosis fungoides/Sezary syndrome involving the peripheral blood. However, CD26 expression by reactive and neoplastic T cells in solid tissues and body fluids has not been fully characterized by flow cytometry (FC). Methods Solid tissue and body fluid specimens were assayed for CD26 expression using four-color FC immunophenotyping, by qualitative assessment of population clusters, and by quantitation with comparison with isotype controls. Benign T cells were studied in reactive tissues and in the background of other malignancies. Results Many T-cell lymphomas were dim or negative for CD26, whereas a few were brightly positive. In the majority of T-cell lymphomas, CD26 expression could potentially help identify aberrant population clusters. T cells in reactive tissue specimens and tumor-infiltrating T cells were commonly dim to negative for CD26. Conclusions Both T-cell lymphomas and reactive T cells in tissue and body fluid specimens often show low levels of CD26 expression. Therefore, quantitative methods may not reliably distinguish benign from neoplastic T cells in these specimens. However, CD26, in combination with other T-cell markers, can be helpful for identifying aberrant population clusters in T-cell lymphomas. © 2008 Clinical Cytometry Society [source] Performance of the Panleucogating protocol for CD4+ T cell enumeration in an HIV dedicated laboratory facility in Barbados,,CYTOMETRY, Issue S1 2008Namrata Sippy-Chatrani Abstract Objective: To compare the Panleucogating (PLG) protocol with the routinely used four-color protocol for CD4+ T cell count enumeration. Design and Methods: One hundred fifty-three blood samples were randomly selected from samples received at the National HIV Laboratory for routine immunological monitoring. Samples were prepared using Coulter CYTO-STAT® tetraCHROME monoclonal antibodies and FlowCAREÔ PLG CD4 reagent for four-color and PLG, respectively, and analyzed on the Beckman Coulter EPICS XL flow cytometer. The PLG protocol used a sequential gating strategy where CD4+ T cells were identified using side scatter properties of cells and CD45 staining. The four-color protocol used CD45 and CD3 to identify CD4+ T cells. Results: Absolute CD4+ T cell counts and percentages ranged from 4 to 1,285 cells/,L and 0.9 to 46.7%, respectively. Linear regression analyses revealed good correlation of PLG with the four-color protocol (absolute counts, R2 = 0.95; percentages, R2 = 0.98) over the entire range including the clinically relevant range. Bland Altman statistics revealed no bias for CD4 counts <500 cells/,L and a slight underestimation by PLG for counts >500 cells/,L (Bias = ,32.7 cells/,L; 95% agreement limits = ,151.3, +86.0). CD4+ T cell percentages were the similar over the entire range (Bias = 0.6%; 95% agreement limits = ,1.97 ± 3.18). Conclusions: PLG is an accurate method for enumerating CD4+ T cells and has resulted in major cost savings to the Government of Barbados. This has implications for the sustainability of the National HIV containment program in Barbados and the other resource limited Caribbean countries. The PLG technique is now being routinely used in Barbados. © 2008 Clinical Cytometry Society [source] Processing and presentation of (pro)-insulin in the MHC class II pathway: the generation of antigen-based immunomodulators in the context of type 1 diabetes mellitusDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 4 2010Timo Burster Abstract Both CD4+ and CD8+ T lymphocytes play a crucial role in the autoimmune process leading to T1D. Dendritic cells take up foreign antigens and autoantigens; within their endocytic compartments, proteases degrade exogenous antigens for subsequent presentation to CD4+ T cells via MHC class II molecules. A detailed understanding of autoantigen processing and the identification of autoantigenic T cell epitopes are crucial for the development of antigen-based specific immunomodulators. APL are peptide analogues of auto-immunodominant T cell epitopes that bind to MHC class II molecules and can mediate T cell activation. However, APL can be rapidly degraded by proteases occurring in the extracellular space and inside cells, substantially weakening their efficiency. By contrast, protease-resistant APL function as specific immunomodulators and can be used at low doses to examine the functional plasticity of T cells and to potentially interfere with autoimmune responses. Here, we review the latest achievements in (pro)-insulin processing in the MHC class II pathway and the generation of APL to mitigate autoreactive T cells and to activate Treg cells. Copyright © 2010 John Wiley & Sons, Ltd. [source] Phenotypic and genetic analyses of T-cell-mediated immunoregulation in patients with Type 1 diabetesDIABETIC MEDICINE, Issue 10 2006Y. Tsutsumi Abstract Aims To investigate the contribution of regulatory T cells and co-stimulatory molecules in CD4+ T cells to the development of Type 1 diabetes (T1D). Methods Twelve patients with T1D, nine patients with systemic lupus erythematosus (SLE), and 12 age-matched healthy control subjects participated. We analysed the proportions of CD25+CD4+ T cells and natural killer T cells (NKT cells), and the expression levels of Foxp3, CTLA-4, CD28, ICOS, PD-1 and BTLA in peripheral blood mononuclear cells and purified CD4+ T cells. Results There were no significant differences in the proportions of CD25+ CD4+ T cells or NKT cells among the three groups. PD-1 expression levels of peripheral CD4+ T cells from T1D patients were significantly lower than those from healthy control subjects (P = 0.00066). In contrast, PD-1 expression levels were similar in SLE patients and healthy control subjects. The expression levels of Foxp3, CTLA-4, CD28, ICOS and BTLA were similar in the three groups. Conclusions Decreased expression of the PD-1 gene in CD4+ T cells may contribute to the development and/or maintenance of autoimmune T1D. As the population studied was small and heterogeneous, further studies are required to confirm the findings. [source] Impaired nutritional status in common variable immunodeficiency patients correlates with reduced levels of serum IgA and of circulating CD4+ T lymphocytesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2001M. Muscaritoli Background Common variable immunodeficiency (CVI) is a primary defect of the immune system. Infections, persistent diarrhoea and malabsorption may result in malnutrition, which may in turn contribute to increased morbidity. In this paper, the prevalence of malnutrition in CVI was evaluated. Patients and methods Forty CVI patients (20 male, 20 female, aged 17,75 years) underwent anthropometric measurements from which body mass index, arm fat and muscle area were calculated. Body mass index values <,18·5 and arm fat and muscle area values <,10th percentile were considered indicative of malnutrition. Patients were divided into four groups according to circulating CD4+ T cells (lower or greater than 300 µL,1) and serum immunoglobulin A (IgA) levels (detectable and undetectable). Results Body mass index <,18·5, arm fat and muscle area <,10th percentile were observed in 23%, 58% and 44%, respectively, of patients. Lower values of body mass index, arm fat and muscle area were more frequent in patients with low CD4+ cells and undetectable IgA. Low arm fat values were more frequent in patients with diarrhoea (P = 0·03). Infectious episodes were more frequent in undetectable IgA than in detectable IgA patients (P = 0·04). Conclusions Anthropometric measurements revealed an increased rate of malnutrition in CVI patients, particularly in those with low CD4+ and undetectable IgA, suggesting that selected CVI subjects could be considered for standard or specialized nutritional support. [source] New drug combinations for the treatment of murine AIDS and macrophage protectionEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2001A. Fraternale The failure of highly active antiretroviral therapies (HAART) is mainly due to the existence of latent infected reservoirs, such as macrophages and resting CD4+ T cells. In this paper, we report the results that we obtained in a murine model of AIDS by alternating the administration of the lympholitic drug 2-Fluoro-ara-AMP (Fludarabine) to eliminate the infected cells, with that of Azidothymidine (AZT) plus reduced glutathione (GSH) encapsulated in erythrocytes, to protect lymphocytes and macrophages not yet infected, respectively. Two groups of infected mice were treated as follows: one group was treated by alternating the administration of Fludarabine and AZT (treatment A), while the other group received the same treatment plus GSH-loaded erythrocytes given with AZT (treatment A + L,RBC). Fludarabine was administered intraperitoneally, AZT in the drinking water and GSH was encapsulated in erythrocytes by a procedure of hypotonic dialysis and isotonic resealing. The results obtained show that GSH-loaded erythrocytes provide additive effects in all the parameters examined. Alternation of a lympholitic drug and antiretroviral drug is effective in reducing the progression of murine AIDS. Addition of a system to protect macrophages provides additive effects in almost all the parameters considered, confirming that combination therapies aimed at protecting different infectable cell compartments are better than treatments protecting mainly lymphocytes. [source] Alpha2beta1 integrin is the major collagen-binding integrin expressed on human Th17 cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Marc Boisvert Abstract Growing evidence indicates that collagen-binding integrins are important costimulatory molecules of effector T cells. In this study, we demonstrate that the major collagen-binding integrin expressed by human Th17 cells is alpha2beta1 (,2,1) or VLA-2, also known as the receptor for collagen I on T cells. Our results show that human naïve CD4+ T cells cultured under Th17 polarization conditions preferentially upregulate ,2,1 integrin rather than ,1,1 integrin, which is the receptor for collagen IV on T cells. Double staining analysis for integrin receptors and intracellular IL-17 showed that ,2 integrin but not ,1 integrin is associated with Th17 cells. Cell adhesion experiments demonstrated that Th17 cells attach to collagen I and collagen II using ,2,1 integrin but did not attach to collagen IV. Functional studies revealed that collagens I and II but not collagen IV costimulate the production of IL-17A, IL-17F and IFN-, by human Th17 cells activated with anti-CD3. These results identify ,2,1 integrin as the major collagen receptor expressed on human Th17 cells and suggest that it can be an important costimulatory molecule of Th17 cell responses. [source] Chitin induces upregulation of B7-H1 on macrophages and inhibits T-cell proliferationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Claudia J. Wagner Abstract Chitin is a highly abundant glycopolymer, which serves as structural component in fungi, arthropods and crustaceans but is not synthesized by vertebrates. However, vertebrates express chitinases and chitinase-like proteins, some of which are induced by infection with helminths suggesting that chitinous structures may be targets of the immune system. The chitin-induced modulations of the innate and adaptive immune responses are not well understood. Here, we demonstrate that intranasal administration of OVA and chitin resulted in diminished T-cell expansion and Th2 polarization as compared with OVA administration alone. Chitin did not promote nor attenuate Th2 polarization in vitro. Chitin-exposed macrophages inhibited proliferation of CD4+ T cells in a cell,cell contact-dependent manner. Chitin induced upregulation of the inhibitory ligand B7-H1 (PD-L1) on macrophages independently of MyD88, TRIF, TLR2, TLR3, TLR4 and Stat6. Inhibition of T-cell proliferation was largely dependent on B7-H1, as the effect was not observed in cocultures with cells from B7-H1-deficient mice. [source] Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2010Jean-Marie Ramirez Abstract Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo[3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-,, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4+ T cells. The specific AHR-inhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4+ T cells to produce IL-22 without IL-17 and IFN-,. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161+ Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4+ T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. [source] Innate, antigen-independent role for T cells in the activation of the immune system by Propionibacterium acnesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2010Sandrine Tchaptchet Abstract Propionibacterium acnes is a human commensal but also an opportunistic pathogen. In mice, P. acnes exerts strong immunomodulatory activities, including formation of intrahepatic granulomas and induction of LPS hypersensitivity. These activities are dependent on P. acnes recognition via TLR9 and subsequent IL-12-mediated IFN-, production. We show that P. acnes elicits IL-12p40 and p35 mRNA expression in macrophages, and IFN-, mRNA in liver CD4+ T cells and NK cells. After priming with P. acnes, CD4+ T cells serve as the major IFN-, mRNA source. In the absence of CD4+ T cells, CD8+ T cells (regardless of antigenic specificity) or NK cells can produce sufficient IFN-, to induce the P. acnes -driven immune effects. Moreover, in the absence of ,,T cells, ,,T cells also enable the development of strongly enhanced TNF-, and IFN-, responses to LPS and intrahepatic granuloma formation. Thus, under microbial pressure, different T-cell types, independent of their antigen specificity, exert NK-cell-like functions, which contribute decisively to the activation of the innate immune system. [source] HIV-1 impairs in vitro priming of naïve T cells and gives rise to contact-dependent suppressor T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2010Karlhans F. Che Abstract Priming of T cells in lymphoid tissues of HIV-infected individuals occurs in the presence of HIV-1. DC in this milieu activate T cells and disseminate HIV-1 to newly activated T cells, the outcome of which may have serious implications in the development of optimal antiviral responses. We investigated the effects of HIV-1 on DC,naïve T-cell interactions using an allogeneic in vitro system. Our data demonstrate a dramatic decrease in the primary expansion of naïve T cells when cultured with HIV-1-exposed DC. CD4+ and CD8+ T cells showed enhanced expression of PD-1 and TRAIL, whereas CTLA-4 expression was observed on CD4+ T cells. It is worth noting that T cells primed in the presence of HIV-1 suppressed priming of other naïve T cells in a contact-dependent manner. We identified PD-1, CTLA-4, and TRAIL pathways as responsible for this suppresion, as blocking these negative molecules restored T-cell proliferation to a higher degree. In conclusion, the presence of HIV-1 during DC priming produced cells with inhibitory effects on T-cell activation and proliferation, i.e. suppressor T cells, a mechanism that could contribute to the enhancement of HIV-1 pathogenesis. [source] Stress-activated dendritic cells interact with CD4+ T cells to elicit homeostatic memoryEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Yufei Wang Abstract Evidence is presented that thermal or oxidizing stress-activated DC interact with CD4+ T cells to induce and maintain a TCR-independent homeostatic memory circuit. Stress-activated DC expressed endogenous intra-cellular and cell surface HSP70. The NF-,B signalling pathway was activated and led to the expression of membrane-associated IL-15 molecules. These interacted with the IL-15 receptor complex on CD4+ T cells, thus activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T-cell proliferation and IFN-, production. CD40 ligand on CD4+ T cells in turn re-activated CD40 molecules on DC, inducing DC maturation and IL-15 expression thereby maintaining the feedback circuit. The proliferating CD4+ T cells were characterized as CD45RA, CD62L+ central memory cells, which underwent homeostatic proliferation. The circuit is independent of antigen and MHC-class-II-TCR interaction as demonstrated by resistance to TCR inhibition by ZAP70 inhibitor or MHC-class II antibodies. These findings suggest that stress can activate a DC-CD4+ T-cell interacting circuit, which may be responsible for maintaining a homeostatic antigen-independent memory. [source] Natural killer cells become tolerogenic after interaction with apoptotic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2010Wai Po Chong Abstract NK cells are effectors in innate immunity and also participate in immunoregulation through the release of TGF-,1 and lysis of activated/autoreactive T cells. Apoptotic cells (AC) have been shown to induce tolerogenic properties in innate immune cells, including macrophages and dendritic cells, but not NK cells. In this study, we demonstrated that after interaction with AC, NK cells released TGF-,1, which in turn suppressed the production of IFN-, by NK cells upon IL-12 and IgG activation. We further identified phosphatidylserine as a potential target on AC for the NK cells, as phosphatidylserine could stimulate NK cells to release TGF-,1, which in turn suppressed CD4+ T-cell proliferation and activation. Moreover, AC-treated NK cells displayed cytotoxicity against autologous-activated CD4+ T cells by upregulating NKp46. This lysis occurred in part through the NKp46-vimentin pathway, as activated CD4+ T cells expressed vimentin on the cell surface and blocking of vimentin or NKp46, but not other NK-cell receptors, significantly suppressed the NK-cell cytotoxicity. We report here a novel interaction between NK cells and AC, resulting in the tolerogenic properties of NK cells required for immune contraction. [source] Impaired CD4+ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010William F. Carson Abstract Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to alterations in myeloid cell function; however, the effect of severe sepsis on subsequent CD4+ T-cell responses remains unclear. In the present study, CD4+ T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro. CD4+CD62L+ T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4+CD62L+ T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing with exogenous cytokines, indicating a decreased capability of these cells to commit to either the TH1 or TH2 lineage. Repressive histone methylation marks were also evident at promoter regions for the TH1 cytokine IFN-, and the TH2 transcription factor GATA-3 in naïve CD4+ T cells from CLP mice. These results provide evidence that CD4+ T-cell subsets from post-septic mice exhibit defects in activation and effector function, possibly due to chromatin remodeling proximal to genes involved in cytokine production or gene transcription. [source] In vitro -induced Th17 cells fail to induce inflammation in vivo and show an impaired migration into inflamed sitesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2010Marko Janke Abstract Recently, IL-17 produced by Th17 cells was described as pro-inflammatory cytokine with an eminent role in autoimmune diseases, e.g. rheumatoid arthritis. A lack of IL-17 leads to amelioration of collagen-induced arthritis. IL-17 induction in naïve CD4+ T cells depends on IL-6 and TGF-, and is enhanced by IL-23. The in vivo inflammatory potential of in vitro -primed Th17 cells however, remains unclear. Here, we show that, although IL-17 neutralisation results in amelioration of murine OVA-induced arthritis, in vitro -primed Th17 cells cannot exacerbate arthritic symptoms after adoptive transfer. Furthermore, Th17 cells cannot induce an inflammatory delayed type hypersensitivity reaction because they fail to migrate into inflamed sites, possibly due to the lack of CXCR3 expression. Also, re-isolated Th17 cells acquired IFN-, expression, indicating instability of the Th17 phenotype. Taken together, the data show that IL-6, TGF-, and IL-23 might not provide sufficient signals to induce "fully qualified" Th17 cells. [source] Phenotypic analysis of human peripheral blood regulatory T cells (CD4+FOXP3+CD127lo/,) ex vivo and after in vitro restimulation with malaria antigensEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2010Olivia C. Finney Abstract Regulatory T cells (Treg) play crucial roles in regulating autoimmune responses and immunity to tumors and infectious diseases. However, numerous subpopulations of Treg are now being described and the utility of various Treg markers is being reassessed. Here we report the results of a detailed phenotypic comparison of two supposedly regulatory human T-cell populations, namely CD4+FOXP3+ T cells and CD4+CD25hi T cells. We find that CD4+FOXP3+ cells are extremely heterogeneous with respect to CD25 expression and that FOXP3+ and CD25hi CD4+ T cells differ in their expression of chemokine receptors (CCR), CD95 and Bcl-2, suggestive of distinct migration characteristics and susceptibility to apoptosis. Further, we propose that CD25 expression should be regarded as an activation marker rather than as a defining marker of Treg. Lastly, CD4+FOXP3+ T cells activated in vitro with malaria antigen expressed the highest levels of CCR4 and CD95, and the lowest levels of CCR7, indicating that they are most likely generated from effector memory cells during an immune response and rapidly succumb to apoptosis at the end of the response. [source] Cell contact interaction between adipose-derived stromal cells and allo-activated T lymphocytesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2009Monique E. Quaedackers Abstract Mesenchymal stromal cells regulate immune cell function via the secretion of soluble factors. Cell membrane interactions between these cell types may play an additional role. Here, we demonstrate that subpopulations of allo-activated T cells are capable of binding to human adipose-derived stromal cells (ASC). The bound T-cell population contained CD8+ T cells and was enriched for CD4,CD8, T cells, whereas the proportion of CD4+ T cells was decreased compared with the non-bound T-cell population. Bound CD4+ T cells had high proliferative activity and increased CD25 and FoxP3 expression. However, they also expressed CD127, excluding regulatory T-cell function. In CD8+ T cells, IL-2 sensitivity, as determined by the analysis of phosphorylated STAT5, was lower in the presence of ASC and even lower in bound cells. In contrast, IL-2-induced phosphorylated STAT5 levels were higher in bound CD4+ T cells than in non-bound CD4+ T cells. Additionally, pro-proliferative TGF-, signalling via endoglin and SMAD1/5/8 phosphorylation was detected in bound CD4+ T cells. Even after prolonged co-culture with ASC, the activated phenotype of bound CD4+ T cells persisted. In conclusion, these results demonstrate that the binding of lymphocytes to ASC represents an immunomodulatory mechanism in which CD8+ T cells are inhibited in their responsiveness to pro-inflammatory stimuli and reactive CD4+ T cells are depleted from the immune response. [source] Multiple functions of human T cells generated by experimental malaria challengeEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Stephen M. Todryk Abstract Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-,, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum -infected RBC (iRBC) Ag, 28 and 90,days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-, cultured ELISPOT, were low and unstable over time, despite CD4+ T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-,, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-, measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed. [source] Depletion of tumor-induced Treg prior to reconstitution rescues enhanced priming of tumor-specific, therapeutic effector T cells in lymphopenic hostsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Christian H. Poehlein Abstract We reported previously that vaccination of reconstituted, lymphopenic mice resulted in a higher frequency of tumor-specific effector T cells with therapeutic activity than vaccination of normal mice. Here, we show that lymphopenic mice reconstituted with spleen cells from tumor-bearing mice (TBM), a situation that resembles the clinical condition, failed to generate tumor-specific T cells with therapeutic efficacy. However, depletion of CD25+ Treg from the spleen cells of TBM restored tumor-specific priming and therapeutic efficacy. Adding back TBM CD25+ Treg to CD25, naïve and TBM donor T cells prior to reconstitution confirmed their suppressive role. CD25+ Treg from TBM prevented priming of tumor-specific T cells since subsequent depletion of CD4+ T cells did not restore therapeutic efficacy. This effect may not be antigen-specific as three histologically distinct tumors generated CD25+ Treg that could suppress the T-cell immune response to a melanoma vaccine. Importantly, since ex vivo depletion of CD25+ Treg from TBM spleen cells prior to reconstitution and vaccination fully restored the generation of therapeutic effector T cells, even in animals with established tumor burden, we have initiated a translational clinical trial of this strategy in patients with metastatic melanoma. [source] Curcumin induces the tolerogenic dendritic cell that promotes differentiation of intestine-protective regulatory T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Yingzi Cong Abstract The gut is home to a large number of Treg, with both CD4+ CD25+ Treg and bacterial antigen-specific Tr1 cells present in normal mouse intestinal lamina propria. It has been shown recently that intestinal mucosal DC are able to induce Foxp3+ Treg through production of TGF-, plus retinoic acid (RA). However, the factors instructing DC toward this mucosal phenotype are currently unknown. Curcumin has been shown to possess a number of biologic activities including the inhibition of NF-,B signaling. We asked whether curcumin could modulate DC to be tolerogenic whose function could mimic mucosal DC. We report here that curcumin modulated BM-derived DC to express ALDH1a and IL-10. These curcumin-treated DC induced differentiation of naïve CD4+ T cells into Treg resembling Treg in the intestine, including both CD4+CD25+ Foxp3+ Treg and IL-10-producing Tr1 cells. Such Treg induction required IL-10, TGF-, and retinoic acid produced by curcumin-modulated DC. Cell contact as well as IL-10 and TGF-, production were involved in the function of such induced Treg. More importantly, these Treg inhibited antigen-specific T-cell activation in vitro and inhibited colitis due to antigen-specific pathogenic T cells in vivo. [source] IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ memory T cells in chronic colitisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009Takayuki Tomita Abstract We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4+CD45RBhigh T cells into IL-7,/,×RAG-1,/, mice did not induce colitis; and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7,/,×RAG-1,/, mice parabiosed with colitic CD4+CD45RBhigh T-cell-transferred RAG-1,/, mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4+ T cells by surgically separating these parabionts. Surprisingly, the separated IL-7,/,×RAG-1,/, mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7,/,×RAG-1,/, partners. CD4+ T cells isolated from the separated RAG-1,/, or IL-7,/,×RAG-1,/, mice were then transferred into new RAG-1,/, or IL-7,/,×RAG-1,/, mice. Regardless of the source of donor cells, RAG-1,/, recipients developed colitis, whereas IL-7,/,×RAG-1,/, recipients did not. Collectively, these results demonstrate that IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ T cells rather than the maintenance of those cells in established colitic mice. They also provide a basis for the timing of IL-7/IL-7R blockade for the treatment of inflammatory bowel diseases. [source] Efficient help for autoreactive B-cell activation requires CD4+ T-cell recognition of an agonist peptide at the effector stageEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2009Brian D. Hondowicz Abstract T-cell recognition of peptide/MHC complexes is flexible and can lead to differential activation, but how interactions with agonist (full activation) or partial agonist (suboptimal activation) peptides can shape immune responses in vivo is not well characterized. We investigated the effect of stimulation by agonist or partial agonist ligands during initial CD4+ T-cell priming, and subsequent T-B-cell cognate interactions, on antibody production by anti-chromatin B cells. We found that autoantibody production required TCR recognition of an agonist peptide at the effector stage of B-cell activation. However, interaction with a weak agonist ligand at this effector stage failed to promote efficient autoantibody production, even if the CD4+ T cells were fully primed by an agonist peptide. These studies suggest that the reactivity of the TCR for a target self-peptide during CD4+ T-B-cell interaction can be a critical determinant in restraining anti-chromatin autoantibody production. [source] T-bet protects against exacerbation of schistosome egg-induced immunopathology by regulating Th17-mediated inflammationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2009Laura I. Rutitzky Abstract C57BL/6 mice infected with Schistosoma mansoni naturally develop mild CD4+ T-cell-mediated immunopathology characterized by small hepatic granulomas around parasite eggs. However, immunization with soluble egg Ag in CFA markedly exacerbates the lesions by inducing a potent proinflammatory environment with high levels of IFN-, and IL-17, which are signature cytokines of distinct Th1- versus Th17-cell lineages. To determine the relative role of these subsets in disease exacerbation, we examined mice deficient in T-bet (T-bet,/,), which is required for Th1 differentiation and IFN-, production. We now report that immunization with soluble egg Ag in CFA caused a significantly greater enhancement of egg-induced hepatic immunopathology in T-bet,/, mice compared with WT controls, and analysis of their granulomas disclosed a higher proportion of activated DC and CD4+ T cells, as well as a marked influx of neutrophils. The absence of IFN-, in the T-bet,/, mice correlated with a marked increase in IL-23p19, IL-17 and TNF-, in granulomas and MLN. In contrast, T-bet,/, mice had lower levels of IL-4, IL-5 and IL-10 and a reduction in FIZZ1 and FoxP3 expression, suggesting diminished regulatory activity, respectively, by alternatively activated macrophages and Treg. These findings demonstrate that T-bet-dependent signaling negatively regulates Th17-mediated immunopathology in severe schistosomiasis. [source] | ||||||||||||||||||||||||||||||||||