Home About us Contact
|
Home About us Contact | ||
|
|
||
Th1 Cells (th1 + cell)
Selected AbstractsStepwise regulation of TH1 responses in autoimmunity: IL-12-related cytokines and their receptorsINFLAMMATORY BOWEL DISEASES, Issue 8 2005Christoph Becker PhD Abstract Interleukin (IL)-12 is a key cytokine of cell-mediated immune responses. Until recently, IL-12 was believed to be unique in its ability to induce the differentiation of naive T cells toward the TH1 phenotype and in its pathogenic activity, as shown in various disease models including inflammatory bowel disease. However, recently, 2 additional cytokines closely related to IL-12, IL-23 and IL-27, were discovered. Until then, the role of IL-12 was overestimated because it was believed that the p40 subunit was unique to IL-12. The discovery that IL-12 shares p40 with IL-23 and that IL-23 but not IL-12 is essential in models of chronic inflammation and autoimmunity led to a model in which IL-12 is essential to induce interferon-,-producing TH1 cells, whereas IL-23 mediates effector functions. The latest cytokine added to this cytokine family is IL-27. IL-27 has the unique feature to act on naive T cells, rendering them susceptible to IL-12 signaling. Thus, IL-27 may be essential for the early events of a cell-mediated immune response. This review focuses on these novel cytokines and their role in cell-mediated immune responses and discusses differences and common features within the family of IL-12-related cytokines. [source] Autologous nucleus pulposus primes T cells to develop into interleukin-4-producing effector cells: An experimental study on the autoimmune properties of nucleus pulposusJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 1 2009Andrea Geiss Abstract An autoimmune response to herniated nucleus pulposus has been proposed to constitute a pathophysiologic mechanism for inducing sciatica based on the fact that nucleus pulposus under normal conditions is excluded from the development of immunological tolerance. The manifestation of an autoimmune response comprises different steps starting with antigen capture, continuing with activation of T helper (TH) cells and ending with production of autoantibodies. Activated TH cells differentiate into either TH1 cells, predominately producing proinflammatory cytokines such as interferon , (IFN,) or a TH2 subset mainly producing anti-inflammatory cytokines such as interleukin-4 (IL-4). The aim of the present study was to examine if exposure of autologous nucleus pulposus (NP) to the immune system for 3 weeks is potent enough to prime TH cells to differentiate into TH2 cells. The study was performed in a pig model allowing the exposure of NP to the immune system. To assess the polarization of TH cells the intracellular production of IFN, and IL-4 was measured in T cells by using flow cytometry. The revealed predominant production of IL-4 together with low production of IFN, in T cells after NP exposure to the immune system indicates that nucleus pulposus may prime TH cells to develop into IL-4-producing TH2 cells after being exposed to the immune system, for example, in association with disc herniation. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:97,103, 2009 [source] TLR2-independent induction and regulation of chronic intestinal inflammationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2010Olivier Boulard Abstract Interactions between the intestinal microflora and host innate immune receptors play a critical role in intestinal homeostasis. Several studies have shown that TLR2 can modulate inflammatory responses in the gut. TLR2 signals enhance tight junction formation and fortify the epithelial barrier, and may play a crucial role in driving acute inflammatory responses towards intestinal bacterial pathogens. In addition, TLR2 agonists can have direct effects on both Th1 cells and Treg. To define the role of TLR2 in the induction and regulation of chronic intestinal inflammation we examined the effects of TLR2 deletion on several complementary models of inflammatory bowel disease. Our results show that TLR2 signals are not required for the induction of chronic intestinal inflammation by either innate or adaptive immune responses. We further show that TLR2,/, mice harbor normal numbers of Foxp3+ Treg that are able to suppress intestinal inflammation as effectively as their WT counterparts. We also did not find any intrinsic role for TLR2 for pathogenic effector T-cell responses in the gut. Thus, in contrast to their role in acute intestinal inflammation and repair, TLR2 signals may have a limited impact on the induction and regulation of chronic intestinal inflammation. [source] Human Th17 cells: Are they different from murine Th17 cells?EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2009Francesco Annunziato Abstract Type 17 Th (Th17) cells have been identified as a distinct population of CD4+ effector T cells different from Th1 and Th2 cells. While the pre-eminent cytokine of Th1 cells is IFN-, and that of Th2 cells is IL-4, the distinctive cytokine of Th17 cells is IL-17A. However, although murine and human Th1 and Th2 cells exhibit strong similarities, human and murine Th17 cells seem to differ in several aspects. [source] Breakpoints in immunoregulation required for Th1 cells to induce diabetesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006Margaret Neighbors Abstract We describe a novel TCR-transgenic mouse line, TCR7, where MHC class,II-restricted, CD4+ T cells are specific for the subdominant H-2b epitope (HEL74,88) of hen egg lysozyme (HEL), and displayed an increased frequency in the thymus and in peripheral lymphoid compartments over that seen in non-transgenic littermate controls. CD4+ T cells responded vigorously to HEL or HEL74,88 epitope presented on APC and could develop into Th1 or Th2 cells under appropriate conditions. Adoptive transfer of TCR7 Ly5.1 T cells into Ly5.2 rat insulin promoter (RIP)-HEL transgenic recipient hosts did not lead to expansion of these cells or result in islet infiltration, although these TCR7 cells could expand upon transfer into mice expressing high levels of HEL in the serum. Islet cell infiltration only occurred when the TCR7 cells had been polarized to either a Th1 or Th2 phenotype prior to transfer, which led to insulitis. Progression from insulitis to autoimmune diabetes only occurred in these recipients when Th1 but not Th2 TCR7 cells were transferred and CTLA-4 signaling was simultaneously blocked. These findings show that regulatory pathways such as CTLA-4 can hold in check already differentiated autoreactive effector Th1 cells, to inhibit the transition from tolerance to autoimmune diabetes. See accompanying commentary at http://dx.doi.org/10.1002/eji.200636591 [source] NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-, secretionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006Barbara Morandi Abstract Human secondary lymphoid tissues harbor NK cells that predominantly secrete cytokines in response to activation. Here, we demonstrate that these immunoregulatory NK cells assist in the Th1 polarization of primary immune responses, induced by dendritic cells. Tonsilar, but not peripheral blood NK cells enhanced the expansion of IFN-,-producing CD4+ T cells via their superior ability to produce IFN-,. Addition of IFN-, increased Th1 polarization while antibody blocking of this cytokine abolished NK cell-dependent Th1 polarization. Our data suggest that NK cells in secondary lymphoid organs assist priming of Th1 cells via cytokine secretion and this effect should be harnessed during vaccination against viruses and tumors. [source] IFN-,-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKLEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2005Shigeru Kotake Abstract The current study explored our hypothesis that IFN-,-producing human T cells inhibit human osteoclast formation. Activated T cells derived from human PBMC were divided into IFN-,-producing T cells (IFN-,+ T cells) and IFN-,-non-producing T cells (IFN-,, T cells). IFN-,+ T cells were cultured with human monocytes in the presence of macrophage-CSF alone. The concentration of soluble receptor activator of NF-,B ligand (RANKL) and IFN-,, and the amount of membrane type RANKL expressed on T cells, were measured by ELISA. In the patients with early rheumatoid arthritis (RA) treated with non-steroidal anti-inflammatory drugs alone, CD4+ T cells expressing both IFN-, and RANKL were detected by flow cytometry. Surprisingly, IFN-,+ T cells, but not IFN-,, T cells, induced osteoclastogenesis from monocytes, which was completely inhibited by adding osteoprotegerin and increased by adding anti-IFN-, antibodies. The levels of both soluble and membrane type RANKL were elevated in IFN-,+ T cells. The ratio of CD4+ T cells expressing both IFN-, and RANKL in total CD4+ T cells from PBMC was elevated in RA patients. Contrary to our hypothesis, IFN-,+ human T cells induced osteoclastogenesis through the expression of RANKL, suggesting that Th1 cells play a direct role in bone resorption in Th1 dominant diseases such as RA. [source] Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004Susannah Abstract To address how heritable patterns of gene expression are acquired during the differentiation of Th1 and Th2 cells, we analyzed the nuclear position of lineage-restricted cytokine genes and their upstream regulators by 3-dimensional fluorescence in situ hybridization. During Th1 differentiation, GATA-3 and c-maf loci, which encode upstream regulators of Th2 cytokines, were progressively repositioned to centromeric heterochromatin as defined by a ,-satellite repeat probe and/or the nuclear periphery, compartments that have been associated with transcriptional repression. A third transcription factor locus, T-bet, which controls Th1-specific programs, was subject to de novo CpG methylation in a Th2 cell clone. In contrast, we did not find repositioning of the cytokine gene loci IL-2, IL-3, IL-4 or IFN-, during T helper cell differentiation. Instead, IFN-, was constitutively associated with the nuclear periphery, even when primed for expression in Th1 cells. Our results suggest that Th1/Th2 lineage commitment and differentiation involve repositioning of the regulators of cytokine expression, rather than the cytokine genes themselves. [source] Microbial Toll-like receptor ligands differentially regulate CXCL10/IP-10 expression in fibroblasts and mononuclear leukocytes in synergy with IFN-, and provide a mechanism for enhanced synovial chemokine levels in septic arthritisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2003Paul Proost Abstract The CXC chemokine IFN-,-inducible protein-10 (IP-10/CXCL10) activates CXC chemokine receptor 3 (CXCR3) and attracts activated T cells and natural killer cells. Peripheral blood mononuclearcells (PBMC) produce low but significant amounts of IP-10/CXCL10 protein upon stimulation with double-stranded (ds) RNA, the Toll-like receptor 3 (TLR3) ligand. IFN-, is a superior IP-10/CXCL10inducer. The bacterial TLR4 and TLR2 ligands, LPS and peptidoglycan (PGN), inhibit IFN-,- or dsRNA-dependent IP-10/CXCL10 production in PBMC, whereas IL-8/CXCL8 production was enhanced. In fibroblasts a different picture emerges with IFN-, inducing moderate and dsRNA provoking strong IP-10/CXCL10 production. Furthermore, treatment of fibroblasts with IFN-, in combination with bacterial LPS or PGN results in a synergistic production of IP-10/CXCL10 and IL-8/CXCL8. The synergistic induction of IP-10/CXCL10 in fibroblasts is reflected by significantly enhanced IP-10/CXCL10 concentrations in synovial fluids of septic compared to osteoarthritis patients to reach on average higher levels than those of IL-8/CXCL8. These high amounts of IP-10/CXCL10 produced by connective tissue fibroblasts not only attract CXCR3 expressing activated Th1 cells and natural killer cells to sites of infection but may also antagonize the CCR3 dependent attraction of Th2 lymphocytes and exert CXCR3-independent, defensin-like antibacterial activity. [source] The development of effector and memory T cells in cutaneous leishmaniasis: the implications for vaccine developmentIMMUNOLOGICAL REVIEWS, Issue 1 2004Phillip Scott Summary:,Leishmania major infections induce the development of a CD4+ T-helper 1 (Th1) response that not only controls the primary infection but also results in life-long immunity to reinfection. How that immunity is maintained is unknown, although because of the existence of infection-induced immunity, there has been an assumption that the development of a vaccine against leishmaniasis would be relatively easy. This has turned out not to be the case. One problem has been the finding that a large part of the immunity induced by a primary infection depends upon the presence of persistent parasites. Nevertheless, there are ample situations where immunologic memory persists without the continued presence of antigen, providing the prospect that a non-live vaccine for leishmaniasis can be developed. To do so will require an understanding of the events involved in the development of an effective protective T-cell response and, more importantly, an understanding of how to maintain that response. Here, we review work from our laboratory, describing how Th1 cells develop in L. major -infected mice, the nature of the memory T cells that provide protection to reinfection, and how that information may be utilized in the development of vaccines. [source] Control of IL-4 expression in T helper 1 and 2 cellsIMMUNOLOGY, Issue 4 2008Jane Gilmour Summary The mechanism of differentiation of naďve T cells to a variety of effector lineages, but particularly to T helper type 1 (Th1) and Th2 cells, has been the subject of intense scrutiny over the past two decades. Studies have revealed that the expression of cytokines, receptors, signalling molecules, transcription factors, DNA methylating enzymes and histone-modifying enzymes is altered during the process and has been shown to play a co-ordinated role to facilitate expression of the cytokines interleukin-4 (IL-4), IL-5 and IL-13 in Th2 cells, or interferon-, in Th1 cells. Regulation of IL-4 expression has been of particular interest for two main reasons: first because IL-4 acts as a growth factor for Th2 cells, and second because of its role in the induction of immunoglobulin class switching to immunoglobulin E, which plays a critical role in mediating allergic responses. Study of the pathways that promote this tissue-restricted expression of IL-4 may highlight potential areas for therapeutic intervention. [source] Prostaglandin E2 is a negative regulator on human plasmacytoid dendritic cellsIMMUNOLOGY, Issue 1 2006Yonsu Son Summary Prostaglandin E2 (PGE2), a major lipid derived from the metabolism of arachidonic acid, is an environmentally bioactive substance produced by inflammatory processes and acts as a cAMP up-regulator that plays an important role in immune responses. It has been reported that PGE2 has the ability to inhibit the production of interleukin-12 by myeloid dendritic cells (MDCs) and macrophages, and then induce preferential T helper type 2 (Th2) cell responses. However, little is known of the function of PGE2 for plasmacytoid dendritic cells (PDCs), which may contribute to the innate and adaptive immune response to viral infection, allergy and autoimmune diseases. In the present study, we compared the biological effect of PGE2 on human PDCs and MDCs. PGE2 caused the death of PDCs but MDCs survived. Furthermore, we found that, whereas PGE2 inhibited interferon-, production by PDCs in response to virus or cytosine,phosphate,guanosine, it inhibited interelukin-12 production by MDCs in response to lipopolysaccharide (LPS) or poly(I:C). Although both virus-stimulated PDCs and LPS-stimulated MDCs preferentially induced the development of interferon-,-producing Th1 cells, pretreatment with PGE2 led both DC subsets to attenuate their Th1-inducing capacity. These findings suggest that PGE2 represents a negative regulator on not only MDCs but also PDCs. [source] Interleukin-4 supports interleukin-12-induced proliferation and interferon-, secretion in human activated lymphoblasts and T helper type 1 cellsIMMUNOLOGY, Issue 1 2006Martin A. Kriegel Summary Interleukin-12 (IL-12) and IL-4 are known to differentially promote T helper (Th) cell differentiation. While IL-12 induces interferon-, (IFN-,) production and maturation of Th1 cells, IL-4 is thought to antagonize IL-12 and to favour Th2 development. Here we studied the combined action of various concentrations of common ,-chain (,c -chain) cytokines, including IL-4 and the Th1 cytokine IL-12, in human activated lymphoblasts and Th1 cells. IL-4 and IL-7 potentiated IL-12-induced proliferation at every concentration tested (1,10 ng/ml) without increasing rescue from apoptosis, indicating that proliferation was directly affected by these cytokine combinations. With regards to cytokine secretion, IL-2 together with IL-12 initiated tumour necrosis factor-, synthesis, enhanced IFN-, production, and shedding of soluble IL-2 receptor , as expected. Importantly, combining IL-4 with IL-12 also enhanced IFN-, secretion in lymphoblasts and a Th1 cell line. Investigating signal transduction in lymphoblasts induced by these cytokines, we found that not only IL-2 but also IL-4 enhances signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation by IL-12. Tyrosine phosphorylations of janus kinase 2 (JAK-2), tyrosine kinase 2 (TYK2), extracellular signal-regulated kinase (ERK) and STAT4, STAT5 and STAT6 were not potentiated by combinations of these cytokines, suggesting specificity for increased STAT3 phosphorylation. In conclusion, two otherwise antagonizing cytokines co-operate in activated human lymphoblasts and Th1 cells, possibly via STAT3 as a converging signal. These data demonstrate that IL-4 can directly enhance human Th1 cell function independently of its known actions on antigen-presenting cells. These findings should be of importance for the design of cytokine-targeted therapies of human Th-cell-driven diseases. [source] Reciprocal activating interaction between 6-sulfo LacNAc+ dendritic cells and NK cellsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2009Rebekka Wehner Abstract Dendritic cells (DCs) display an extraordinary capacity to induce T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Additional findings indicate that DCs may also play a crucial role for the activation of natural killer (NK) cells, which are important effectors in innate antitumor immunity. However, studies investigating the interaction between native human DCs and NK cells are limited. Recently, we defined 6-sulfo LacNAc (slan) DCs as a major subpopulation of myeloid human blood DCs, which represent principal producers of the proinflammatory cytokines tumor necrosis factor-, and interleukin (IL)-12. Functional data revealed that slanDCs efficiently induce neoantigen-specific CD4+ T cells and activate tumor-reactive cytotoxic T cells. When evaluating the crosstalk between slanDCs and NK cells in this study, we found that lipopolysaccharide (LPS)-activated slanDCs efficiently enhance NK cell CD69 expression and interferon (IFN)-, secretion. NK cell-mediated tumor-directed cytotoxicity was significantly improved by slanDCs. NK cell activation induced by slanDCs was critically dependent on IL-12. When investigating the impact of NK cells on the immunostimulatory capacity of slanDCs, we observed that they promote DC maturation. In addition, NK cells strongly enhanced the secretion of immunomodulatory IL-12 and reduced the release of immunosuppressive IL-10 by slanDCs. IFN-, and cell-to-cell contact contributed to these effects. Furthermore, data revealed that DC-NK cell crosstalk improves slanDC-mediated differentiation of naďve CD4+ T lymphocytes into IFN-,-producing Th1 cells. In conclusion, we demonstrate a reciprocal activating interaction between slanDCs and NK cells, which may play a pivotal role in the regulation of antitumor immunity. © 2008 Wiley-Liss, Inc. [source] Recognition of coagulation factor VIII by CD4+ T cells of healthy humansJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2003G-L. Hu Summary., Hemophilia A patients treated with coagulation factor (F)VIII may develop an anti-FVIII immune response. Anti-FVIII antibodies may occur also in healthy subjects. To understand the extent to which an immune response to FVIII occurs in healthy subjects, we investigated the proliferative response of blood CD4+ T cells from 90 blood donors to FVIII and to pools of overlapping synthetic peptides spanning the sequences of individual FVIII domains (A1,A3, C1,C2). Most subjects responded to FVIII and several FVIII domains. Men had stronger responses to FVIII than women, and older subjects than younger subjects. The domain-induced responses were weaker than the FVIII-induced responses, yet their intensity in individual subjects correlated with that of the response to FVIII. We examined whether Th1 and/or Th2 cells responded to FVIII in 68 subjects, by determining the CD4+ T cells that secreted interferon-, (IFN-,) or interleukin (IL)-5 after stimulation with FVIII: 25 subjects had FVIII-specific IFN-,-secreting cells, and seven of them had also FVIII-specific IL-5-secreting cells. None had only IL-5-secreting cells. Thus, a CD4+ T cell response to FVIII, which first involves Th1 cells, is common among subjects with a normal procoagulant function. [source] Allergen-induced in vitro expression of IL-18, SLAM and GATA-3 mRNA in PBMC during sublingual immunotherapyALLERGY, Issue 8 2007J. Savolainen Background:, Signalling lymphocytic activation molecule (SLAM) and interleukin (IL)-18 induce interferon (IFN)-, production from Th1 cells. The allergen-induced SLAM and IL-18 mRNA expressions are increased during subcutaneous immunotherapy (SCIT), but nothing is known about their role during sublingual immunotherapy (SLIT). Transcription factor GATA-3 is associated with Th2 cells but its role in SCIT and SLIT is yet unexplored. This study was undertaken to analyse the allergen induced in vitro mRNA expression of IL-18, SLAM and GATA-3 in peripheral blood mononuclear cells (PBMC) of children with allergic rhinitis (AR) during SLIT. Methods:, Ten patients with AR undergoing pollen SLIT with a weekly dose of 200 000 SQ-U, 10 with 24 000 SQ-U of mixture of Betula verrucosa, Corylus avellana and Alnus glutinosa and 10 with placebo were included. Peripheral blood mononuclear cell were stimulated with birch extract prior to, after 1 and 2 years of the treatment. The mRNA expression was assessed using kinetic real-time RT-PCR (TaqMan®; Applied Biosystems, Foster City, CA, USA). Results:, The expression of IL-18 mRNA was increased in the high-dose group in comparison to the placebo group after 1 year of therapy (P = 0.028) and had an inverse correlation with the late phase skin reaction after the second study year (r = ,0.41, P = 0.041). SLAM mRNA expression increased in the high-dose group from baseline to 1 year (P = 0.028) and correlated with IL-10 (r = 0.96, P < 0.0001) and transforming growth factor-, (r = 0.80, P = 0.0037) mRNA expression. No significant changes were seen in GATA-3 mRNA expression. Conclusions:, During SLIT, IL-18 and SLAM are upregulated, suggesting that the Th2 type inflammatory response is downregulated during SLIT by increased Th1 type response. [source] T-cell activation in occupational asthma and rhinitisALLERGY, Issue 2 2007E. Mamessier Background:, Allergic asthma and rhinitis are described as associated with a Th2 activation. However, recent works indicate that a Th1 activation can also be associated with these diseases, concomitantly to a defect in regulatory T (Treg) cell activation. Occupational asthma (OA) and occupational rhinitis (OR) are peculiar cases of these diseases in which the T-cell activation profile is largely unknown. Objective:, To characterize T-cell activation induced after a specific inhalation test (SIT) in OA and OR. Material and methods:, A total of 21 subjects with OA, 10 subjects with OR, 10 exposed nonallergic (ENA) subjects, and 14 healthy volunteers were included. The SIT with the incriminated substance was performed in patients and ENA subjects. Blood and induced sputum were obtained before and after SIT. T cells were analysed for CD69, CD25, IL-13, and IFN- , expression by flow cytometry. IL-4 and IFN- , were assayed by enzyme-linked immunosorbent assay (ELISA) in cell culture supernatants. Treg cells were identified as CD4+CD25+highCD45RO+CD69, T cells in peripheral blood. Results:, Baseline IFN- , production was decreased in OA and OR compared with controls. The SIT induced an increase in both Th1 and Th2 cells in blood and sputum from OA. In this group, the proportion of peripheral Treg cells decreased after SIT. Similar results were found in the CD8+ population. ELISA assays were concordant with flow cytometry. In OR, an attenuated activation profile was found, with an increase in the proportion of IL-13-producing T cells after SIT. By contrast, in ENA subjects, SIT induced Th2 activation, with an increase in Treg cells and a decrease in Th1 cells. Conclusions:, Our results demonstrate a gradient of T-cell activation from a tolerating profile in ENA subjects to an inflammatory profile in OA, with an intermediate stage in OR. [source] T lymphocytes expressing CCR3 are increased in allergic rhinitis compared with non-allergic controls and following allergen immunotherapyALLERGY, Issue 1 2007J. N. Francis Background:, In T cell-associated allergic inflammation, homing of T-helper 2 (Th2) effector cells to mucosal sites may be influenced by chemokine receptor expression. Previous studies have identified CCR3 and CCR4 as putative markers of Th2 cells and CCR5 and CXCR3 as markers of Th1 cells. The aim of this study was to assess differential chemokine receptor expression from symptomatic atopic grass pollen-sensitive subjects, compared with patients on high-dose allergen injection immunotherapy (IT) and healthy controls. Methods:, We examined chemokine receptor expression (CCR1,7 and CXCR1,4) by flow cytometry of peripheral blood CD4+ and CD8+ T cells. We also depleted peripheral blood mononuclear cell (PBMC) populations of CCR3+ CD4+ cells by magnetic bead separation and cells were stimulated with grass pollen allergen for 6 days. Cytokine production was measured by enzyme-linked immunosorbent assay. Results:, On freshly isolated PBMC, atopic individuals exhibited increased numbers of CCR3+ CD4+ cells compared with normal controls (P < 0.01). CCR3 expression in IT patients was reduced compared with matched atopic rhinitic controls (P < 0.05) and comparable with that observed in normal subjects. Depletion of CCR3+ CD4+ cells from allergen-stimulated PBMC cultures resulted in decreased interleukin (IL)-5 production compared with whole CD4+ populations (P < 0.05). Freshly isolated CCR3+ CD4+ cells have significantly higher intracellular IL-4 and lower IFN- , levels than CCR3, CD4+ cells. CD4+ T cells cultured from both peripheral cells and nasal biopsies demonstrated increased expression of CCR3 in the presence of IL-4 (P < 0.05). Conclusion:, CCR3+ CD4+ T cells are increased in allergic rhinitis, are reduced by allergen IT, have a Th2 phenotype and contribute to allergen-specific responses. Strategies against CCR3+ T cells may be effective in human allergic diseases. [source] Review: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity , a tale of conflict and conundrumNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 5 2010M. Müller M. Müller, S. Carter, M. J. Hofer and I. L. Campbell (2010) Neuropathology and Applied Neurobiology36, 368,387 The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity , a tale of conflict and conundrum The chemokines CXCL9, CXCL10 and CXCL11 (also known as monokine induced by interferon-,, interferon-inducible protein-10 and interferon-inducible T cell ,-chemoattractant, respectively) are structurally and functionally related molecules within the non-ELR CXC chemokine subgroup. These chemokines are generally not detectable in most non-lymphoid tissues under physiological conditions but are strongly induced by cytokines, particularly interferon-,, during infection, injury or immunoinflammatory responses. CXCL9, CXCL10 and CXCL11 each bind to a common primary receptor, CXCR3, and possibly to additional receptors. They are best known for their role in leucocyte trafficking, principally acting on activated CD4+ Th1 cells, CD8+ T cells and NK cells. An abundance of data demonstrates that CXCL9, CXCL10 and CXCL11 are produced in many diverse pathologic conditions of the central nervous system. More recent attention has focussed on the function of these chemokines in the central nervous system inflammation. The results of these studies have proven to be sometimes surprising and other times contradictory. Here we discuss the likely more subtle and perhaps divergent roles for these chemokines in the pathogenesis of neuroinflammatory diseases. [source] ORIGINAL ARTICLE: Imbalance of T-cell Transcription Factors Contributes to the Th1 Type Immunity Predominant in Pre-eclampsiaAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2010Zhou Jianjun Problem, Extensive studies have demonstrated that Th1 type immunity is predominant in pre-eclampsia, but there is little concern with regard to the intracellular mechanisms behind this initial T-cell polarization. In this study, we investigated whether the imbalance of the T-cell transcription factors contributes to it. Method of study, A total of 15 pre-eclamptic patients and 15 healthy pregnant women were enrolled in this study. The expression levels of transcription factors for Th1 (T-bet), Th2 (GATA3), Th17 (RORc) and Treg (FOXP3) cells, together with the Th1/Th2 status, were simultaneously investigated in both peripheral blood mononuclear cells (PBMCs) and decidua. Results, The expression levels of FOXP3 mRNA were decreased in both PBMCs and decidua from pre-eclamptic patients compared with healthy pregnant women (P < 0.05), and T-bet mRNA and RORc mRNA were significantly increased (P < 0.05), while Th1/Th2 balance shifted toward the Th1 immunity. Furthermore, there was a negative correlation between FOXP3 mRNA and Th1 cells (P < 0.05), and the expression level of T-bet mRNA correlated strongly with Th1 cells (P < 0.05). Conclusion, Decreased expression of FOXP3 mRNA and increased expression of T-bet mRNA may contribute to Th1 type immunity predominant in pre-eclampsia. [source] Recruitment of CXCR3+ and CCR5+ T Cells and Production of Interferon-,-Inducible Chemokines in Rejecting Human ArteriesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2005William R. Burns Chemokine receptors preferentially expressed by Th1 cells and their IFN-,-inducible ligands predominate in experimental and clinical allograft rejection. Previous chemokine-related transplantation studies have focused on parenchymal and microvascular inflammation which are of importance in acute rejection, but are not necessarily relevant in immune-mediated injury of conduit arteries. We have recently described a model of progressive human T cell-mediated infiltration and injury of allogeneic coronary artery segments using immunodeficient mouse hosts. In the present study, we investigated if recruitment of allogeneic T cells to different vascular compartments correlated with the expression of chemokines and their receptors. Transcripts were quantified by laser capture microdissection/real-time RT-PCR and their distribution was correlated to the corresponding protein expression detected by immunohistochemistry. Infiltrating T cells, confined to the adventitia and intima, expressed CXCR3 and CCR5, but were not recruited into the media despite production by vascular smooth muscle cells of IP-10, Mig, I-TAC, RANTES and MIP-1,. Chemokine mRNA was detected primarily in vascular cells, although chemokine protein largely localized to infiltrating leukocytes which uniquely expressed their cognate receptors. These data explain the recruitment of IFN-,-secreting T cells to the vessel wall, and reinforce the suggestion that the arterial media may be a site of immunological privilege. [source] T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-,,ANNALS OF NEUROLOGY, Issue 5 2009Luca Durelli MD Objective T-helper 1 (Th1) and Th17 lymphocytes are involved in experimental autoimmune encephalomyelitis, the model of multiple sclerosis (MS). We characterized the Th1/Th17 cell populations in peripheral blood (PB), their interferon (IFN) receptor expression sensitivity to IFN-, in MS patients. Methods In 30 untreated patients with active MS (AMS) and 32 with inactive MS (IMS), and in 22 healthy subjects, we measured intracellular cytokine expression, interleukin-17,producing myelin basic protein,stimulated PB lymphocytes, surface IFN type I receptor chain1 (IFN-,R1) expression, IFN-,-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation, and apoptosis of anti-CD3 monoclonal antibody,stimulated PB lymphocytes. Results Th17 cell percentage increased around sevenfold in AMS compared with IMS or healthy subjects, but there was no change in Th1 cells. Th17 cells in AMS were myelin basic protein specific. The longitudinal follow-up of 18 MS patients shifting between AMS and IMS showed that the percentage of Th17 but not Th1 cells always increased in AMS. IFN-,R1 expression, IFN-,,induced STAT1 activation, and apoptosis were significantly greater in Th17 than Th1 cells. IFN-,R1 expression and IFN-,,dependent STAT1 activation progressively increased in vitro with a highly significant positive correlation only in developing Th17 but not in Th0 or Th1 cells. Interpretation Evidence that an expansion of peripheral Th17 cells, a Th subset that can infiltrate brain parenchyma and damage cells, is associated with disease activity in MS. The greater IFN-,R1 level expressed by Th17 compared with Th1 cells might make them a selective target for IFN-, therapy. Ann Neurol 2009;65:499,509 [source] Treg cell numbers and function in patients with antibiotic-refractory or antibiotic-responsive lyme arthritisARTHRITIS & RHEUMATISM, Issue 7 2010Shiqian Shen Objective In a murine model of antibiotic-refractory Lyme arthritis, the numbers of Treg cells are dramatically reduced. The aim of this study was to examine Treg cell numbers and function in patients with antibiotic-refractory Lyme arthritis. Methods CD4+ T cell subsets were enumerated in the peripheral blood (PB) and synovial fluid (SF) of 12 patients with antibiotic-refractory arthritis and 6 patients with antibiotic-responsive arthritis. Treg cell function was examined using Borrelia -specific and nonspecific Treg cell proliferation assays. Results In both patient groups, interferon-,,positive Th1 cells in SF were abundant and enriched (,50% of CD4+ T cells). In patients with antibiotic-refractory arthritis, the median percentages of FoxP3-positive Treg cells were significantly higher in SF than in PB (12% versus 6%; P = 0.03) or in SF from patients with antibiotic-responsive arthritis (12% versus 5%; P = 0.04). Moreover, in the antibiotic-refractory group, a higher percentage of Treg cells in SF correlated with a shorter duration until resolution of arthritis (r = ,0.74, P = 0.006). In contrast, patients with fewer Treg cells had suboptimal responses to disease-modifying antirheumatic drugs and a longer duration of arthritis after antibiotic treatment, and they often required synovectomies for arthritis resolution. In each group, Treg cells in SF dampened Borrelia burgdorferi,specific proliferative responses, and in 2 patients with antibiotic-refractory arthritis, Treg cells were functional in nonspecific suppression assays. Conclusion Treg cells were functional in patients with antibiotic-refractory arthritis, and in some patients, higher numbers of these cells in SF appeared to participate in arthritis resolution. However, as in the murine model, patients with antibiotic-refractory arthritis and lower numbers of Treg cells seemed unable to achieve resolution of synovial inflammation. [source] Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 2 2010Heidi Kokkonen Objective To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA). Methods A nested case,control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre-patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system. Results The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin-1, [IL-1,], IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon-,, IL-12), Th2 cells (IL-4, eotaxin), Treg cells (IL-10), bone marrow,derived factors (IL-7, granulocyte,macrophage colony-stimulating factor, and granulocyte colony-stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1,). The levels were particularly increased in anti,cyclic citrullinated peptide antibody, and rheumatoid factor,positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL-17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell,related cytokines, while chemokines, stromal cell,derived cytokines, and angiogenic-related markers separated patients after the development of RA from individuals before the onset of RA. Conclusion Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell,related factors); after disease onset, the involvement and activation of the immune system was more general and widespread. [source] Gamma/delta T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 8 2009Yoshinaga Ito Objective Although interleukin-17 (IL-17),producing ,/, T cells were reported to play pathogenic roles in collagen-induced arthritis (CIA), their characteristics remain unknown. The aim of this study was to clarify whether ,/, T cells or CD4+ T cells are the predominant IL-17,producing cells, and to determine what stimulates ,/, T cells to secret IL-17 in mice with CIA. The involvement of IL-17,producing ,/, T cells in SKG mice with autoimmune arthritis and patients with rheumatoid arthritis (RA) was also investigated. Methods IL-17,producing cells in the affected joints of mice with CIA were counted by intracellular cytokine staining during 6 distinct disease phases, and these cells were stimulated with various combinations of cytokines or specific antigens to determine the signaling requirements. Similar studies were performed using SKG mice with arthritis and patients with RA. Results Gamma/delta T cells were the predominant population in IL-17,producing cells in the swollen joints of mice with CIA, and the absolute numbers of these cells increased in parallel with disease activity. IL-17,producing ,/, T cells expressed CC chemokine receptor 6, were maintained by IL-23 but not by type II collagen in vitro, and were induced antigen independently in vivo. Furthermore, IL-17 production by ,/, T cells was induced by IL-1, plus IL-23 independently of T cell receptor. In contrast to what was observed in mice with CIA, IL-17,producing ,/, T cells were nearly absent in the affected joints of SKG mice and patients with RA, and Th1 cells were predominant in the joints of patients with RA. Conclusion Gamma/delta T cells were antigen independently stimulated by inflammation at affected joints and produced enhanced amounts of IL-17 to exacerbate arthritis in mice with CIA but not in SKG mice with arthritis or patients with RA. [source] Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cellsARTHRITIS & RHEUMATISM, Issue 4 2009Manuel A. González Objective Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Adult mesenchymal stem cells (MSCs) were recently found to suppress effector T cell responses and to have beneficial effects in various immune disorders. The purpose of this study was to examine a new therapeutic strategy for RA based on the administration of human adipose-derived MSCs (AD-MSCs). Methods DBA/1 mice with collagen-induced arthritis were treated with human AD-MSCs after disease onset, and clinical scores were determined. Inflammatory response was determined by measuring the levels of different mediators of inflammation in the joints and serum. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen. The number of Treg cells and the suppressive capacity on self-reactive Th1 cells were also determined. Results Systemic infusion of human AD-MSCs significantly reduced the incidence and severity of experimental arthritis. This therapeutic effect was mediated by down-regulating the 2 deleterious disease components: the Th1-driven autoimmune and inflammatory responses. Human AD-MSCs decreased the production of various inflammatory cytokines and chemokines, decreased antigen-specific Th1/Th17 cell expansion, and induced the production of antiinflammatory interleukin-10 in lymph nodes and joints. Human AD-MSCs also induced de novo generation of antigen-specific CD4+CD25+FoxP3+ Treg cells with the capacity to suppress self-reactive T effector responses. Conclusion Human AD-MSCs emerge as key regulators of immune tolerance by inducing the generation/activation of Treg cells and are thus attractive candidates for a cell-based therapy for RA. [source] GATA-3 protects against severe joint inflammation and bone erosion and reduces differentiation of Th17 cells during experimental arthritisARTHRITIS & RHEUMATISM, Issue 3 2009Jan Piet van Hamburg Objective Rheumatoid arthritis is associated with the infiltration of T helper cells into the joints. It is unclear whether interferon-, (IFN,),producing Th1 cells or the novel T helper subset, interleukin-17 (IL-17),producing Th17 cells, are the pathogenic mediators of joint inflammation in chronic nonautoimmune arthritis. Therefore, this study was aimed at examining whether the Th2-specific transcription factor GATA-3 can regulate arthritis, in an experimental murine model, by modulating Th1 and/or Th17 cell polarization. Methods Arthritis was induced with methylated bovine serum albumin (mBSA) in both wild-type and CD2 T cell,specific GATA-3 (CD2,GATA-3),transgenic mice. At days 1 and 7 after the induction of arthritis, knee joints were scored macroscopically for arthritis severity and for histologic changes. Single-cell suspensions were generated from the spleens, lymph nodes, and inflamed knee joints. Cytokine expression by CD4+ T cells was determined using flow cytometry, and IL-17 expression in the inflamed knee joints was determined by enzyme-linked immunosorbent assay. Analyses of gene expression were performed for Th17-associated factors. Results Wild-type mice developed severe joint inflammation, including massive inflammatory cell infiltration and bone erosion that increased significantly over time, reaching maximal arthritis scores at day 7. In contrast, only mild joint inflammation was observed in CD2,GATA-3,transgenic mice. This mild effect was further accompanied by systemic and local reductions in the numbers of IL-17+IFN,, and IL-17+IFN,+, but not IL-17,IFN,+, CD4+ T cells, and by induction of Th2 cytokine expression. Moreover, GATA-3 overexpression resulted in reduced gene expression of the Th17-associated transcription factor retinoic acid,related orphan receptor ,t. Conclusion These results indicate that enforced GATA-3 expression protects against severe joint inflammation and bone erosion in mice, accompanied by reduced differentiation of Th17 cells, but not Th1 cells, during mBSA-induced arthritis. [source] The Critical Role of IL-12p40 in Initiating, Enhancing, and Perpetuating Pathogenic Events in Murine Experimental Autoimmune NeuritisBRAIN PATHOLOGY, Issue 4 2002Lei Bao Interleukin 12 (IL-12) is a proinflammatory cytokine with important immunoregulatory activities and is critical in determining the differentiation and generation of Th1 cells. For the present study, we investigated the role of endogenous IL-12 in the pathogenesis of experimental autoimmune neuritis (EAN), which is a CD4+ T-cell mediated autoimmune inflammatory disease of the peripheral nervous system. EAN is used as an animal model for Guillain-Barré syndrome of humans. Here, EAN was established in IL-12 p40 deficient mutant (IL-12 -/- ) C57BL/6 mice by immunization with P0 peptide 180,199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant. In these IL-12 -/- mice the onset of clinical disease was delayed, and the incidence and severity of EAN were significantly reduced compared to that in wild-type mice. The former group's clinical manifestations were associated with less P0-peptide 180,199 induced secretion of interferon-, (IFN-,) by splenocytes in vitro and low production of anti-P0-peptide 180,199 IgG2b antibodies in serum. Fewer IFN-, and TNF-, producing cells, but more cells secreting IL-4, were found in sciatic nerve sections from IL-12 -/- mice, consistent with impaired Th1 functions and response. However, the IL-12 deficiency appeared not to affect P0 peptide 180,199-specific T-cell proliferation. These results indicate that IL-12 has a major role in the initiation, enhancement and perpetuation of pathogenic events in EAN by promoting a Th1 cell-mediated immune response and suppressing the Th2 response. This information augments consideration of IL-12 as a therapeutic target in Guillain-Barré syndrome and other T-cell-mediated autoimmune diseases. [source] Natural killer T cell-mediated antitumor immune responses and their clinical applicationsCANCER SCIENCE, Issue 9 2006Ken-ichiro Seino A unique lymphocyte population, CD1d-restricted NKT cells, has been revealed to be a key player in both the innate and acquired immune responses, including antitumor effects. Recent studies revealed that at least two subsets of CD1d-restricted NKT cells exist: type I, having invariant V,14 receptor; and type II, having heterogeneous non-V,14 receptor. The specific glycolipid ligand, ,-GalCer, effectively stimulates mouse and human type I NKT cells. The activation of type I NKT cells substantially influences function of other various cell types, particularly DC, NK cells, CD4 Th1 cells, and CD8 cytotoxic T cells, all contributing to the antitumor immune responses. Recent studies also indicated that, unlike type I NKT cells, type II NKT cells have a potential to repress antitumor immune responses. In this review, we summarize the characteristics of the antitumor immune responses mediated by both mouse and human CD1d-restricted NKT cells and discuss their potential in clinical applications against cancer. (Cancer Sci 2006; 97: 807,812) [source] Antitumor activity of chimeric immunoreceptor gene-modified Tc1 and Th1 cells against autologous carcinoembryonic antigen-expressing colon cancer cellsCANCER SCIENCE, Issue 9 2006Takeshi Sasaki To generate tumor-specific and interferon (IFN)-,-producing Tc1 and Th1 cells applicable for many cancer patients, we previously developed a protocol for generating carcinoembryonic antigen (CEA)-specific Tc1 and Th1 cells from healthy human T cells by transduction with a lentivirus containing a chimeric immunoglobulin T-cell receptor (cIgTCR) gene composed of single-chain variable fragments from an anti-CEA-specific monoclonal antibody fused to an intracellular signaling domain of CD28 and CD3,. These cells, designated Tc1-T and Th1-T bodies, respectively, showed strong antitumor activity against CEA-expressing tumor cells in RAG2,/, mice when both of them were transferred. However, it remains unclear whether it is possible to generate Tc1-T and Th1-T bodies from cancer patients with defective T-cell function because of significant immunosuppression. Here, we prepared Tc1-T and Th1-T bodies from T cells of a colon cancer patient, and asked whether these T bodies can exert effective T-cell function against autologous tumor cells. These T bodies showed high cytotoxicity and produced IFN-, in response to CEA-expressing autologous tumor cells, even in the presence of soluble CEA. It was also demonstrated that Th1-T bodies supported the survival of Tc1-T bodies through cell-to-cell interactions. Furthermore, our protocol utilized retrovirus for cIgTCR transduction to achieve better induction efficiency compared to lentivirus-mediated transduction. Taken together, our findings here indicate that retrovirally transduced Tc1-T and Th1-T bodies will become a promising strategy for adoptive immunotherapy of human cancer. (Cancer Sci 2006; 97: 920,927) [source] | |||||||||||||||||||||||||||||||