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Costimulatory Molecules (costimulatory + molecule)
Terms modified by Costimulatory Molecules Selected AbstractsA recombinant bispecific single-chain antibody induces targeted, supra-agonistic CD28-stimulation and tumor cell killingEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2003Ludger Grosse-Hovest Abstract Endowing tumor cells with costimulatory signals for T cell activation has emerged as a promising strategy for tumor immunotherapy. Costimulatory molecules were either transfected into tumor cells to generate vaccines or were fused, e.g. to antibodies against tumor-associated antigens, to achieve targeted T cell costimulation in vivo. Here we report the production and purification of rM28, a recombinant bispecific single-chain antibody directed to a melanoma-associated proteoglycan and to the costimulatory CD28 molecule on human T cells. We found that a dimer of the recombinant molecule, bound to tumor target cells, induced pronounced T cell activation in peripheral blood mononuclear cell preparations without additional TCR/CD3 stimulation being required. Thelytic activity generated after 3,days of stimulation effectively prevented tumor cell growth. However, it was unspecific and predominantly mediated by non T cells. Our findings demonstrate that presentation of a CD28 antibody within a suitable recombinant, bispecific format may result in a "targeted supra-agonistic stimulation" of the CD28 molecule, which leads to effective tumor cell killing after induction of unspecifically lytic cells. [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] Enhanced expression of B7-1, B7-2, and intercellular adhesion molecule 1 in sinusoidal endothelial cells by warm ischemia/reperfusion injury in rat liverHEPATOLOGY, Issue 4 2001Naosuke Kojima To elucidate a role of costimulatory molecule and cell adhesion molecule in hepatic ischemia/reperfusion injury, we examined an alteration in B7-1 (CD80), B7-2 (CD86), and intercellular adhesion molecule 1 (ICAM-1; CD54) expression in the rat liver after warm ischemia/reperfusion injury. To induce hepatic warm ischemia in a rat model, both portal vein and hepatic artery entering the left-lateral and median lobes were occluded by clamping for 30 minutes or 60 minutes, and then reperfused for 24 hours. B7-1, B7-2, and ICAM-1 expressions in the liver were analyzed by immunofluorescence staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Although B7-1 and B7-2 expressions were at very low levels in the liver tissues from normal or sham-operated control rats, both B7-1 and B7-2 expressions were enhanced at protein and messenger RNA (mRNA) levels in the affected, left lobes after warm ischemia/reperfusion. ICAM-1 protein and mRNA were constitutively expressed in the liver of normal and sham-operated control rats, and further up-regulated after warm ischemia/reperfusion. Localization of increased B7-1, B7-2, and ICAM-1 proteins, as well as von Willebrand factor as a marker protein for endothelial cells, was confined by immunofluorescence staining to sinusoidal endothelial cells in hepatic lobules. Data from quantitative real-time RT-PCR analysis revealed that B7-1 and B7-2 mRNA levels were elevated in hepatic lobes after warm ischemia/reperfusion (5.13- and 52.9-fold increase, respectively), whereas ICAM-1 mRNA expression was rather constitutive but further enhanced by warm ischemia/reperfusion (4.24-fold increase). These results suggest that hepatic sinusoidal endothelial cells play a pivotal role as antigen-presenting cells by expressing B7-1 and B7-2 in warm hepatic ischemia/reperfusion injury, and that B7-1 and/or B7-2 might be the primary target to prevent early rejection and inflammatory reactions after hepatic ischemia/reperfusion injury associated with liver transplantation. [source] Engagement of the CD137 (4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in collagen-induced arthritis and establishes lasting disease resistanceIMMUNOLOGY, Issue 1 2004Juergen L. Foell Summary Agonistic antibodies against CD137 act as costimulators in the activation of CD8 T cells. They enhance the immune response against syngeneic tumour grafts and suppress T cell-dependent humoral immune responses in vivo. The present study was undertaken to determine whether suppression of antibody production by anti-CD137 mAb affects the development of collagen-induced arthritis (CIA). Male DBA/1J mice were immunized with bovine collagen II (CII) and treated with an agonistic anti-CD137 mAb or an isotype-matched control mAb. Mice were assessed regularly for macro- and microscopic signs of arthritis and for the appearance of collagen-specific antibody production. Interferon (IFN)-, determination, FACS analysis of splenocytes and histopathological joint examinations were performed after the animals were killed. Administration of anti-CD137 mAb at the time of collagen immunization blocked the development of disease and inhibited the humoral immune response against CII. Agonistic anti-CD137 mAb exhibited therapeutic efficacy even after the immune response to CII had succeeded and the disease became apparent. Furthermore, it induced a protective memory in the animals, enabling resistance to subsequent challenges with the pathogenic antigen. Our results suggest a key role for CD137 in the pathogenesis of CIA. This model provides insights into immunoregulatory conditions that control the pathogenesis of autoimmune diseases. [source] Enhanced Osteoclastogenesis in 4-1BB,Deficient Mice Caused by Reduced Interleukin-10,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2006Hyun-Hee Shin PhD Abstract Enhanced osteoclastogenesis was observed in bone marrow,derived macrophage cells from 4-1BB,deficient mice than in those from wildtype mice. 4-1BB and 4-1BB ligand interaction may play a role at a certain stage of osteoclast formation through increased level of IL-10, a negative regulator of osteoclastogenesis. Introduction: 4-1BB is an inducible T-cell costimulatory molecule and a member of the TNF receptor family. The expression pattern of 4-1BB and 4-1BB ligand (4-1BBL) has suggested that 4-1BB plays a role not only in various responses related to innate immunity but also in bone metabolism. Materials and Methods: Osteoclast formation was evaluated in bone marrow,derived macrophage cells (BMMs) from wildtype and 4-1BB,deficient (4-1BB,/,) mice. Expression of interleukin-10 (IL-10) during osteoclast formation was analyzed at the mRNA and protein levels. Results: Expression of IL-10 was higher in RANKL-stimulated wildtype BMMs than 4-1BB,/, BMMs. When 4-1BBL was stimulated with 4-1BB,Fc fusion protein, the expression of IL-10 in BMMs increased. Neutralization of IL-10 was not as effective in preventing inhibition by IL-10 of osteoclast differentiation in 4-1BB,/, BMMs as in wildtype BMMs. When IL-10 was added to the culture medium, osteoclast formation was inhibited more efficiently in the 4-1BB,/, BMMs than in the wildtype BMMs. Conclusions: Interaction of 4-1BB and 4-1BBL stimulates IL-10 production through 4-1BBL signaling. 4-1BBL plays a role at a certain stage of osteoclast formation, and IL-10 may mediate this effect. The elevated level of osteoclastogenesis in 4-1BB,/, BMMs may thus be caused, in part, by a lower level of IL-10. [source] Differential Requirement of CD27 Costimulatory Signaling for Naïve Versus Alloantigen-Primed Effector/Memory CD8+ T CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010K. Yamaura CD8+ memory T cells endanger allograft survival by causing acute and chronic rejection and prevent tolerance induction. We explored the role of CD27:CD70 T-cell costimulatory pathway in alloreactive CD8+/CD4+ T-cell activation. CD27-deficient (CD27,/,) and wild-type (WT) B6 mice rejected BALB/c cardiac allografts at similar tempo, with or without depletion of CD4+ or CD8+ T cells, suggesting that CD27 is not essential during primary T-cell alloimmune responses. To dissect the role of CD27 in primed effector and memory alloreactive T cells, CD27,/, or WT mice were challenged with BALB/c hearts either 10 or 40 days after sensitization with donor-type skin grafts. Compared to WT controls, allograft survival was prolonged in day 40- but not day 10-sensitized CD27,/, recipients. Improved allograft survival was accompanied by diminished secondary responsiveness of memory CD8+ T cells, which resulted from deficiency in memory formation rather than their lack of secondary expansion. Chronic allograft vasculopathy and fibrosis were diminished in CD27,/, recipients of class I- but not class II-mismatched hearts as compared to WT controls. These data establish a novel role for CD27 as an important costimulatory molecule for alloreactive CD8+ memory T cells in acute and chronic allograft rejection. [source] Expression of gp34 (OX40 Ligand) and OX40 on Human T Cell ClonesCANCER SCIENCE, Issue 4 2001Naruhiko Takasawa gp34, which we previously cloned, is a ligand of OX40 (CD 134), a costimulatory molecule involved in T cell activation. To elucidate the role of human OX40/OX40L interaction, we examined the expression of gp34 (OX40L) and OX40 in normal human hematopoietic cells by using flow cytometry. OX40 expression is observed on activated T cells, while OX40L is expressed in antigen-presenting cells. However, cytotoxic T lymphocyte (CTL) clones specific for Epstein-Barr virus (EBV)-transformed autologous lymphoblastic cell lines (LCLs) induced both OX40 and OX40L expression after antigen or T cell receptor (TCR) stimulation. This study suggests a possible function of OX40L/OX40, through T cell-T cell interaction, in the reactivation of memory T cells in an auto-crine manner, with implications for the pathogenesis of viral infections and neoplasms. [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] Antigen-loaded ER microsomes from APC induce potent immune responses against viral infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2009Vassiliki Sofra Abstract Although matured DC are capable of inducing effective primary and secondary immune responses in vivo, it is difficult to control the maturation and antigen loading in vitro. In this study, we show that ER-enriched microsomal membranes (microsomes) isolated from DC contain more peptide-receptive MHC I and II molecules than, and a similar level of costimulatory molecules to, their parental DC. After loading with defined antigenic peptides, the microsomes deliver antigenic peptide,MHC complexes (pMHC) to both CD4 and CD8 T cells effectively in vivo. The peptide-loaded microsomes accumulate in peripheral lymphoid organs and induce stronger immune responses than peptide-pulsed DC. The microsomal vaccines protect against acute viral infection. Our data demonstrate that peptide,MHC complexes armed microsomes from DC can be an important alternative to DC-based vaccines for protection from viral infection. [source] Dendritic cells derived from TBP-2-deficient mice are defective in inducing T cell responsesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2008Aoi Son Abstract Thioredoxin-binding protein-2 (TBP-2), also known as vitamin,D3-up-regulated protein,1 (VDUP1), was identified as an endogenous molecule interacting with thioredoxin (TRX). Here, we show that dendritic cells (DC) derived from TBP-2-deficient mice are defective in the function of T cell activation. To compare TBP-2,/, DC function with wild-type (WT) DC, we stimulated DC with lipopolysaccharide (LPS). Although TBP-2,/, DC and WT DC expressed comparable levels of MHC class,II and costimulatory molecules such as CD40, CD80 and CD86, the IL-12p40, IL-12p70 and IL-6 productions of TBP-2,/, DC were attenuated. In a mixed leukocyte reaction (MLR), the concentrations of IL-2, IFN-,, IL-4 and IL-10 in the culture supernatant of MLR with TBP-2,/, DC were significantly lower than those in the cultures with WT DC. In MLR also, as with LPS stimulation, IL-12p40 and IL-12p70 production from TBP-2,/, DC was less than that from WT DC. Proliferation of T cells cultured with TBP-2,/, DC was poorer than that with WT DC. Invivo delayed-type hypersensitivity responses in TBP-2,/, mice immunized with ovalbumin were significantly reduced compared to WT mice. These results indicate that TBP-2 plays a crucial role in DC to induce T cell responses. [source] Priming of CD8+ T cell responses by pathogens typically depends on CD70-mediated interactions with dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2007Anita Schildknecht Abstract The CD27/CD70-interaction has been shown to provide a costimulatory and survival signal for T cells in vitro and in vivo. Recently, CD70 expression by DC was found to be important for the priming of CD8+ T cells. We show here that blocking CD70 interactions has a significant impact on priming of CD8+ T cell responses by vaccinia virus (VV), Listeria monocytogenes and vesicular stomatitis virus (VSV) in mice. However, the priming of specific CD8+ T cells upon infection with lymphocytic choriomeningitis virus (LCMV) was only marginally reduced by CD70-blockade. Blocking of CD70 prevented CD8+ T cell priming in DIETER mice, a model in which presentation of LCMV-derived epitopes can be induced selectively in dendritic cells (DC). In contrast, CD70-CD27 interactions were not important for the priming of VSV-specific CD4+ T cells or class switch of neutralizing antibodies. As we show that priming of CD8+ T cells by the pathogens used here is dependent on antigen presentation by DC and that infection results in up-regulation of CD70 on DC, we conclude that CD70 expression on DC plays an important role in the priming of CD8+ T cells by pathogens. Moreover, the lack of CD70 cannot be completely compensated for by other costimulatory molecules. [source] The role of the ICOS/B7RP-1 T cell costimulatory pathway in murine experimental autoimmune uveoretinitisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2006Yoshihiko Usui Abstract ICOS/B7RP-1 is a new member of the CD28/B7 family of costimulatory molecules and plays differential roles in autoimmune diseases. In this study, we examined the role of ICOS/B7RP-1 pathway in the pathogenesis of mouse experimental autoimmune uveoretinitis (EAU), an animal model of human autoimmune uveitis. ICOS expression was found on infiltrating CD4+ T cells in the region of the retina in EAU-induced mice. The anti-B7RP-1 monoclonal antibody (mAb)-treated or ICOS-deficient mice showed a substantial reduction of disease scores. Blockade of ICOS/B7RP-1 interaction during the effector phase ameliorated the disease, whereas its blockade during the induction phase exhibited no significant effect. Moreover, administration of anti-B7RP-1 mAb effectively ameliorated the disease induced by adoptive transfer of pathogenic T cells. The anti-B7RP-1 mAb treatment inhibited the expansion and/or effector function of pathogenic T cells, given that proliferative response and IFN-, production by lymph node cells were reduced upon restimulation with the antigen peptide in vitro. These results suggest that the ICOS/B7RP-1 interaction plays a critical role in the pathogenesis of uveitis. We also indicated that ICOS-mediated costimulation plays differential roles in EAU and experimental autoimmune encephalomyelitis, which is also a Th1 disease induced in the same manner as EAU. [source] Modulation of dendritic cell phenotype and functionin an in vitro model of the intestinal epitheliumEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2006Matt Butler Abstract A network of dendritic cells (DC) can be detected in close proximity to the epithelial cells overlying Peyer's patches in the gut. Intestinal DC show distinct phenotypes as compared to DC from the systemic lymph nodes (relatively low MHC and costimulatory molecules and high IL-10 and TGF,) and may play a role in maintaining tolerance to enteric antigens. We show that a similar phenotype is induced in the presence of a polarised epithelial cell monolayer in vitro. Monocyte-derived DC were co-cultured with Caco-2 intestinal epithelial monolayers for 24,h. Co-culture resulted in DC with reduced expression of MHC class,II, CD86, and CD80, and poor T,cell stimulatory capacity. Cytokine profiles showed reduced levels of inflammatory cytokine production, and co-cultured DC were less sensitive to stimulation via Toll-like receptors (TLR2, 4, and 6) as a result of increased levels of autocrine TGF, production. However, phenotypic changes in co-cultured DC could not be blocked by removal of apoptotic cells or addition of anti-TGF, antibodies, suggesting that other soluble factors are involved in DC modulation. Thus, polarised epithelial cell monolayers create a ,tolerogenic' environment which modulates the activity of DC. These results highlight the regulatory importance of the epithelial microenvironment at mucosal surfaces. [source] The immune status of Kupffer cells profoundly influences their responses to infectious Plasmodium berghei sporozoitesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2005Nick Steers Abstract Multi-factorial immune mechanisms underlie protection induced with radiation-attenuated Plasmodia sporozoites (,-spz). Spz pass through Kupffer cells (KC) before invading hepatocytes but the involvement of KC in protection is poorly understood. In this study we investigated whether ,-spz-immune KC respond to infectious spz in a manner that is distinct from the response of naive KC to infectious spz. KC were isolated from (1) naive, (2) spz-infected, (3) ,-spz-immune, and (4) ,-spz-immune-challenged C57BL/6 mice and examined for the expression of MHC class I and II, CD40 and CD80/CD86, IL-10 and IL-12 responses and antigen-presenting cell (APC) function. KC from ,-spz-immune-challenged mice up-regulated class I and costimulatory molecules and produced elevated IL-12p40, relative to naive KC. In contrast, KC from naive mice exposed to infectious spz down-modulated class I and IL-12p40 was undetectable. Accordingly, KC from spz-infected mice had reduced APC function, while KC from ,-spz-immune-challenged mice exhibited augmented APC activity. The nearly opposite responses are consistent with the fact that spz challenge of ,-spz-immune mice results in long-lasting sterile protection, while infection of naive mice always results in malaria. [source] Site-specific expression of CD11b and SIRP, (CD172a) on dendritic cells: implications for their migration patterns in the gut immune systemEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2005Diane Bimczok Abstract Dendritic cells (DC) in the intestinal tract play a major role in directing the mucosal immune system towards tolerance or immunity. We analyzed whether different mucosal DC subsets in pigs have specific functions, localizations, or migration patterns in vivo. Therefore, we collected physiologically migrating DC by pseudo-afferent cannulation of the intestinal duct in eight Göttingen minipigs. Lymph DC were phenotypically and functionally characterized and compared to DC found on histological sections of porcine small intestine and mesenteric lymph nodes (MLN). Four different DC subpopulations were detected. Lamina propria (LP) DC were mainly CD11b+ signal regulatory protein,, (SIRP,)+, DC in Peyer's patches were mainly CD11b,/SIRP,+ in subepithelial domes and CD11b,/SIRP,, in interfollicular regions, whereas MLN DC were largely CD11b+/SIRP,,. Of these four subsets, only the CD11b+/SIRP,+ DC and the CD11b+/SIRP,, DC were present in lymph. This suggests that DC migration to MLN largely originates from the LP. Lymph DC expressed high levels of MHC class,II and costimulatory molecules and had a low capacity for FITC-dextran uptake, indicating a mature phenotype. However, lymph DC did not induce PBMC proliferation in MLR, and migration was not significantly influenced by mucosal antigen application. [source] Kinetics of costimulatory molecule expression by T cells and dendritic cells during the induction of tolerance versus immunity in vivoEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2005Kristin Hochweller Abstract Steady-state dendritic cells (DC) present peptide-MHC complexes to T cells in a tolerogenic manner, presumably because of deficient costimulation. However, it is clear that the path to tolerance involves initial T cell activation, suggesting that the deficit may lie in late-acting costimulatory molecules. With this in mind we have investigated the kinetics of expression of several costimulatory pairs on DC and OVA-reactive T cells after i.v. injection of mice with peptide and LPS (immunity), or peptide alone (tolerance). We find that T cells up-regulate CD154, OX40, RANKL and PD-1 whether they are destined for tolerance or immunity, although there are some differences in the levels and length of expression. In contrast, when analyzing DC, we found that up-regulation of CD80, CD86, CD40, RANK and PDL-1 occurred only when peptide was co-administered with LPS. These data give a picture of the T cell looking for costimulatory cues that are not forthcoming when pMHC is presented by steady-state DC, leading to tolerance. However, we did see a strong and rapid up-regulation of RANKL on T cells that occurred specifically when peptide was given in the absence of LPS, suggesting a possible positive signal influencing the decision between tolerance and immunity. [source] Prevention of diabetes in NOD mice at a late stage by targeting OX40/OX40 ligand interactionsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2004Syamasundar Abstract Autoreactive T,cells play a major role in the development of insulin-dependent diabetes mellitus, suggesting that costimulatory molecules that regulate T,cell responses might be essential for disease progression. In NOD mice, CD28/B7 and CD40/CD40 ligand,(L) interactions control the onset of diabetes from 2 to 4,weeks of age, but blocking these molecules has little effect after this time. Hence, it is possible that other ligand/receptor pairs control a later phase of disease. We now show that OX40 is expressed on CD4 and CD8 T,cells several weeks prior to islet destruction, which is initiated around weeks,12,14, and that OX40L is present on dendritic cells in both secondary lymphoid organs and the pancreas from 11 to 13,weeks of age. Blocking OX40L at 6, 9, or 15,weeks after birth had little effect on disease; however, inhibiting OX40/OX40L interactions at week,12, or continuous treatment from week,12 onwards, significantly reduced the incidence of diabetes. Histological examination showed that islet destruction was prevented and insulitis reduced by targeting OX40L. These studies show that OX40/OX40L interactions form a late checkpoint in diabetes development and suggest that these molecules are realistic targets for therapeutic intervention. [source] Activation of src-family tyrosine kinases by LPS regulates cytokine production in dendritic cells by controlling AP-1 formationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2003Giorgio Napolitani Abstract The role of src-family tyrosine kinases in LPS-induced DC maturation has not been fully addressed. We show that LPS induces activation of c-Src and Lyn in human DC. Inhibition of these kinasesby PP1 uncoupled LPS-induced cytokine production from the up-regulation of costimulatory molecules, resulting in DC still capable of stimulating T cell proliferation but much less efficient in inducing Th1 differentiation. This is the first example of a pharmacological inhibitor able to modulate the capacity of DC to induce a particular type of immune response. Inhibition of src-family kinases impaired phosphorylation and accumulation of c-Jun, leading to reduced formation of AP-1 complexes upon LPS stimulation. Thus, src-kinases control cytokine production in LPS-induced DC maturation through a timely formation of AP-1. [source] Solar-simulating irradiation of the skin of human subjects in vivo produces Langerhans cell responses distinct from irradiation ex vivo and in vitroEXPERIMENTAL DERMATOLOGY, Issue 4 2000J. K. Laihia Abstract: It has been postulated that Langerhans cells (LC) provide tolerogenic signals in the local impairment of cutaneous immune functions and antigen-specific tolerance induced by UV radiation. Studies in vitro and ex vivo have indicated that UV radiation may down-regulate the expression of costimulatory molecules on LC, leading to reduced antigen-presenting function. In contrast, we recently observed an up-regulatory stage in the number of human epidermal LC with induced expression of B7 costimulatory molecules 12,24 h after solar-simulating UV radiation (SSR) in vivo. To examine the apparent discrepancy between the observed human LC responses in vitro, ex vivo and in vivo, we compared the three protocols in a parallel fashion. The intact skin as well as skin explants and epidermal cell suspensions from the same individuals were irradiated with a single erythematogenic dose of SSR. The expression of cell surface markers in the epidermal cells was analysed with flow cytometry 24 h later. The number of CD1a+/HLA-DR+ LC increased post-SSR in vivo by a factor of 2.8±0.4, whereas in irradiated skin explants ex vivo or in cell suspensions in vitro, reduced numbers were seen. HLA-DR expression intensities were found to have increased on DR+ and CD1a+/DR+ cells in vivo. Similarly, SSR induced B7-2 (CD86) expression in CD1a+ cells significantly in vivo (P=0.031) but reduced the expression ex vivo or in vitro. We conclude that the early up-regulatory stage of human LC number and membrane markers, recorded at 24 h after a single exposure to SSR, is exclusively an in vivo phenomenon. [source] Mechanism of T cell tolerance induction by murine hepatic Kupffer cells,HEPATOLOGY, Issue 3 2008Qiang You The liver is known to favor the induction of immunological tolerance rather than immunity. Although Kupffer cells (KC) have been indicated to play a role in liver tolerance to allografts and soluble antigens, the mechanisms involved remain unclear. We hypothesized that KCs could promote immune tolerance by acting as incompetent antigen-presenting cells (APC), as well as actively suppressing T cell activation induced by other potent APCs. The expression of antigen presentation-related molecules by KCs was phenotyped by flow cytometry. The abilities of KCs to act as APCs and to suppress T cell activation induced by splenic dendritic cells (DC) were examined by in vitro proliferation assays using CD4+ OVA-TCR (ovalbumin T cell receptor) transgenic T cells. We found that, compared with DCs, KCs expressed significantly lower levels of major histocompatibility complex (MHC) II, B7-1, B7-2, and CD40. This result is consistent with our observation that KCs were not as potent as DCs in eliciting OVA-specific T cell proliferation. However, KCs isolated from polyinosinic:polycytidylic acid,treated mice expressed significantly higher levels of MHC II and costimulatory molecules than did naïve KCs and could stimulate stronger T cell responses. More importantly, we found that KCs could inhibit DC-induced OVA-specific T cell activation. Further investigation of the underlying mechanism revealed that prostaglandins produced by KCs played an important role. The results ruled out the possible involvement of interleukin-10, nitric oxide, 2,3-dioxygenase, and transforming growth factor , in KC-mediated T cell suppression. Conclusion: Our data indicate that KCs are a tolerogenic APC population within the liver. These findings suggest that KCs may play a critical role in regulating immune reactions within the liver and contributing to liver-mediated systemic immune tolerance. (HEPATOLOGY 2008.) [source] Immune regulation by 4-1BB and 4-1BBL: complexities and challengesIMMUNOLOGICAL REVIEWS, Issue 1 2009Chao Wang Summary:, The tumor necrosis factor receptor family member 4-1BB plays a key role in the survival of activated and memory CD8+ T cells. Depending on the disease model, 4-1BB can participate at different stages and influence different aspects of the immune response, likely due to the differential expression of receptor and ligand relative to other costimulatory molecules. Studies comparing mild versus severe influenza infection of mice suggest that the immune system uses inducible receptors such as 4-1BB to prolong the immune response when pathogens take longer to clear. The expression of 4-1BB on diverse cell types, evidence for bidirectional as well as receptor-independent signaling by 4-1BBL, the unexpected hyperproliferation of 4-1BB-deficient T cells, and complex effects of agonistic anti-4-1BB therapy have revealed additional roles for the 4-1BB/4-1BBL receptor/ligand pair in the immune system. In this review, we discuss these diverse roles of 4-1BB and its ligand in the immune response, exploring possible mechanisms for the observed complexities and implications for therapeutic applications of 4-1BB/4-1BBL. [source] Interferons as pathogenic effectors in autoimmunityIMMUNOLOGICAL REVIEWS, Issue 1 2005Roberto Baccala Summary:, Interferons (IFNs) type-1 (IFN ,/,) and type-II (IFN-,) are the most pleiotropic molecules in the intricate cytokine network. This dominance arises from three crucial factors: (i) initiation of IFN-,/, and IFN-, production at the inception of most innate immune responses, which primes for the ensuing adaptive immune responses, primarily through the sine qua non upregulation of major histocompatibility complex and costimulatory molecules; (ii) magnification of their production and signaling by cross-talk between themselves, and synergistic or antagonistic effects on other cytokines; and (iii) direct or indirect initiation of transcription of hundreds of immunologically relevant genes. Considering that aberrant immune responses against self-molecules seem to depend on the same constituents and pathways as those against exogenous antigens, it follows that IFNs are also major effectors in the pathogenesis of autoimmunity. Here, we review the diverse biological effects of IFNs on the immune system, discuss findings pertaining to the nature of exogenous and endogenous stimuli that might induce IFN production through the engagement of Toll-like receptors, and summarize the detrimental and, in some instances, beneficial effects of IFNs in systemic and organ-specific autoimmune diseases. [source] Regulatory T cells and autoimmune diseaseIMMUNOLOGICAL REVIEWS, Issue 1 2005Silke Paust Summary:, Although T-cell clones bearing T-cell receptors with high affinity for self-peptide major histocompatibility complex (MHC) products are generally eliminated in the thymus (recessive tolerance), the peripheral T-cell repertoire remains strongly biased toward self-peptide MHC complexes and includes autoreactive T cells. A search for peripheral T cells that might exert dominant inhibitory effects on autoreactivity has implicated a subpopulation of CD4+CD25+ T cells called regulatory T cells (Tregs). Here, we discuss the role of cytokines and costimulatory molecules in the generation, maintenance, and function of Tregs. We also summarize evidence for the involvement of Tregs in controlling autoimmune diseases, including type 1 diabetes, experimental autoimmune encephalomyelitis, and inflammatory bowel disease. Last, we discuss our recent definition of the potential role of B7 expressed on activated T-effector cells as a target molecule for Treg-dependent suppression. These observations suggest that the engagement of B7 on effector T cells transmits an inhibitory signal that blocks or attenuates effector T-cell function. We restrict our comments to the suppression mediated by cells within the CD4 lineage; the impact of the cells within the CD8 lineage that may suppress via engagement of Qa-1 on effector T cells is not addressed in this review. [source] Memory T-cell trafficking: new directions for busy commutersIMMUNOLOGY, Issue 2 2010Federica M. Marelli-Berg Summary The immune system is unique in representing a network of interacting cells of enormous complexity and yet being based on single cells travelling around the body. The development of effective and regulated immunity relies upon co-ordinated migration of each cellular component, which is regulated by diverse signals provided by the tissue. Co-ordinated migration is particularly relevant to the recirculation of primed T cells, which, while performing continuous immune surveillance, need to promptly localize to antigenic sites, reside for a time sufficient to carry out their effector function and then efficiently leave the tissue to avoid bystander damage. Recent advances that have helped to clarify a number of key molecular mechanisms underlying the complexity and efficiency of memory T-cell trafficking, including antigen-dependent T-cell trafficking, the regulation of T-cell motility by costimulatory molecules, T-cell migration out of target tissue and fugetaxis, are reviewed in this article. [source] Cord blood mesenchymal stem cells propel human dendritic cells to an intermediate maturation state and boost interleukin-12 production by mature dendritic cellsIMMUNOLOGY, Issue 4 2009Lieke C. J. Van Den Berk Summary Pathogen-derived entities force the tissue-resident dendritic cells (DCs) towards a mature state, followed by migration to the draining lymph node to present antigens to T cells. Bone marrow mesenchymal stem cells (MSCs) modulate the differentiation, maturation and function of DCs. In umbilical cord blood an immature MSC population was identified. Remarkably, these immature stem cells modulated DCs in a different way. Marker expression was unchanged during the differentiation of monocytes towards immature DCs (iDCs) when cocultured with cord blood MSC [unrestricted somatic stem cells (USSCs)]. The maturation to mature DCs (mDCs) was enhanced when DCs were co-cultured with USSC, as evidenced by the up-regulation of costimulatory molecules. Endocytosis of dextran by iDCs was hampered in the presence of USSCs, which is indicative for the maturation of iDCs. Despite this maturation, the migration of iDCs cocultured with USSCs appeared to be identical to iDCs cultured alone. However, USSCs increased the migration of mDCs towards CCL21 and boosted interleukin-12 production. So, USSCs mature iDCs, thereby redirecting the antigen-uptake phenotype towards a mature phenotype. Furthermore, DC maturation by lipopolysaccharide (LPS) or USSCs reflects two distinct pathways because migration was unaffected when iDCs were matured by coculture with USSCs, while it was strongly enhanced in the presence of LPS. DCs are able to discriminate the different MSC subtypes, resulting in diverse differentiation programmes. [source] Activated B cells modified by electroporation of multiple mRNAs encoding immune stimulatory molecules are comparable to mature dendritic cells in inducing in vitro antigen-specific T-cell responsesIMMUNOLOGY, Issue 2 2008Jaewoo Lee Summary Ex-vivo -activated B cells are an alternative source of antigen-presenting cells (APCs) and a potential replacement for dendritic cells (DCs) in immunotherapy. However, the ability of ex-vivo -activated B cells to function as potent APCs has been a concern, especially when compared to DCs. Our study investigated whether modification of activated B cells with immune stimulatory molecules could enhance the ability of activated B cells to stimulate T cells. We show that murine splenic B cells, activated with a combination of Toll-like receptor agonist and agonistic anti-CD40, stimulated antigen-specific CD8+ T cells more efficiently than cells activated with Toll-like receptor agonist or anti-CD40 alone, probably by down-regulation of the immune regulatory cytokine interleukin-10 (IL-10). However, the activated B cells were still poor T-cell stimulators compared to mature DCs. Therefore, we modified the activated B cells by simultaneous electroporation of multiple messenger RNAs encoding costimulatory molecules (OX40L and 4-1BBL), cytokines (IL-12p35 and IL-12p40) and antigen. We found that de novo expression or overexpression of OX40L, 4-1BBL and IL-12p70 on activated B cells synergistically enhanced proliferation as well as IL-2 and interferon-, production by CD8+ T cells. Furthermore, the RNA-modified activated B cells induced antigen-specific cytotoxic T lymphocyte responses as efficiently as mature DCs in vitro. Unexpectedly, modified activated B cells were inferior to mature DCs at in vivo induction of CD8+ T-cell responses. In summary, activated B cells modified to express immune stimulatory molecules are a potent alternative to DCs in immunotherapy. [source] Airways infection with virulent Mycobacterium tuberculosis delays the influx of dendritic cells and the expression of costimulatory molecules in mediastinal lymph nodesIMMUNOLOGY, Issue 4 2004Gina S. García-Romo Summary Despite tuberculosis resurgence and extensive dendritic cell (DC) research, there are no in vivo studies evaluating DC within regional lymphoid tissue during airways infection with virulent Mycobacterium tuberculosis (Mtb) H37Rv. Using DC-specific antibodies, immunocytochemistry, flow cytometry and Ziehl,Neelsen (ZN) for bacilli staining, we searched for Mtb and DC changes within mediastinal lymph nodes, after intratracheal (ITT) inoculation of virulent Mtb. ZN and immunocytochemistry in frozen and paraffin sections of mediastinal lymph nodes identified Mtb until day 14 after ITT inoculation, associated with CD11c+ and Dec205+ DC. Analysing CD11c, MHC-CII, and Dec205 combinations by flow cytometry in MLN suspensions revealed that CD11c+/MHC-CII+ and CD11c+/Dec205+ DC did not increase until day 14, peaked on day 21, and sharply declined by day 28. No changes were seen in control, saline-inoculated animals. The costimulatory molecules evaluated in CD11c+ DCs followed a similar trend; the CD80 increase was negligible, slightly surpassed by CD40. CD86 increased earlier and the three markers peaked at day 21, declining by day 28. While antigen-specific proliferation was not evident for MLN CD4+ T cells at 2 weeks postinfection, delayed-type hypersensitivity responses upon ITT inoculation revealed that, as early as day 3 and 7, both the priming and peripheral systemic immune responses were clearly established, persisting until days 14,21. While airways infection with virulent Mtb triggers an early, systemic peripheral response maintained for three weeks, this seems dissociated from regional events within mediastinal lymph nodes, such as antigen-specific T-cell reactivity and a delay in the influx and local activation of DC. [source] Induction of an antitumour adaptive immune response elicited by tumour cells expressing de novo B7-1 mainly depends on the anatomical site of their delivery: the dose applied regulates the expansion of the responseIMMUNOLOGY, Issue 4 2003Silvia Sartoris Summary De novo expression of costimulatory molecules in tumours generally increases their immunogenicity, but does not always induce a protective response against the parental tumour. This issue was addressed in the mouse Sp6 hybridoma model, comparing different immunization routes (subcutaneous, intraperitoneal and intravenous) and doses (0·5 × 106 and 5 × 106 cells) of Sp6 cells expressing de novo B7-1 (Sp6/B7). The results can be summarized as follows. First, de novo expression of B7-1 rendered Sp6 immunogenic, as it significantly reduced the tumour incidence to ,15% with all delivery routes and doses tested, whereas wild-type Sp6 was invariably tumorigenic (100% tumour incidence). Second, long-lasting protection against wild-type Sp6 was mainly achieved when immunization with Sp6/B7 was subcutaneous: a dose of 0·5 × 106 Sp6/B7 cells elicited protection that was confined to sites in the same anatomical quarter as the immunizing injection. Repeated injections of the same dose extended protection against wild-type Sp6 to other anatomical districts, as well as a single injection of a 10-fold higher dose (5 × 106 cells). Finally, Sp6-specific cytotoxic T-lymphocyte activity was detected in draining lymph nodes, and the splenic expansion of Sp6-specific cytotoxic T-lymphocyte precursors quantitatively correlated with the dose of antigen. We conclude that activation of a protective immune response against Sp6 depends on the local environment where the immunogenic form of the ,whole tumour cell antigen' is delivered. The antigen dose regulates the anatomical extent of the protective response. [source] Selective regulation of CD40 expression in murine dendritic cells by thiol antioxidantsIMMUNOLOGY, Issue 2 2003Norifumi Iijima Summary Interaction of CD40 on dendritic cells (DC) with CD40 ligand induces interleukin-12 (IL-12) production by these DC during the antigen presentation. Thus, the level of CD40 expression appears to influence the capability of DC to induce a T helper 1 (Th1) response. However, it is not fully understood how CD40 expression on DC is regulated. In the present study, we examined the effects of the reducing agents, N -acetyl- l -cysteine (NAC) and reduced glutathione (GSH), on tumour necrosis factor-, (TNF-,)-induced phenotypic changes in murine DC. TNF-, markedly increased the expression on DC of major histocompatibility complex (MHC) and the costimulatory molecules, CD40, CD80 and CD86. Both NAC and GSH completely abolished the TNF-,-induced enhancement of CD40 expression, but had no considerable effect on the expression of CD80, CD86 and MHC. The marked decrease of CD40 protein with NAC was also detected by Western blotting, but was not associated with the expression level of CD40 mRNA in DC. Thus, NAC appears to reduce CD40 expression on DC by regulating a post-transcriptional pathway. The inhibitory effect of NAC or GSH on TNF-,-induced CD40 expression was released by simply removing these agents from the culture. In contrast, culture of TNF-,-treated DC with NAC or GSH markedly decreased the expression of CD40 within 12 hr. These results demonstrate that reducing agents selectively, rapidly and reversibly regulate CD40 expression on DC, which may eventually affect the capability of DC for Th1/Th2 polarization. [source] The proportion of CD40+ mucosal macrophages is increased in inflammatory bowel disease whereas CD40 ligand (CD154)+ T cells are relatively decreased, suggesting differential modulation of these costimulatory molecules in human gut lamina propriaINFLAMMATORY BOWEL DISEASES, Issue 11 2006Dr. Hege S. Carlsen MD Abstract Background: Signal transduction through binding of CD40 on antigen-presenting cells and CD40 ligand (CD154) on T cells appears to be crucial for mutual cellular activation. Antibodies aimed at blocking the CD40,CD154 costimulatory pathway dampen the severity of experimental colitis. To elucidate the microanatomical basis for signaling through this costimulatory pathway in human inflammatory bowel disease, we studied in situ the cellular distribution of these 2 molecules on lamina propria macrophages and T cells, respectively. Methods: Colonic specimens from 8 patients with ulcerative colitis and 8 with Crohn's disease, 8 small bowel specimens of Crohn's disease, and histologically normal control samples (6 from colon and 6 from small bowel) were included. Multicolor immunofluorescence in situ staining was performed to determine the percentage of subepithelial macrophages expressing CD40 and that of lamina propria T cells expressing CD154 while avoiding cells in lymphoid aggregates. Results: The proportion of subepithelial CD40highCD68+ macrophages was significantly increased in normal colon compared with normal small bowel and showed further elevation in both colon and small bowel afflicted with inflammatory bowel disease. In addition, on a per-CD68+ -cell basis, CD40 expression was significantly increased in severely inflamed compared with moderately inflamed colonic specimens. Conversely, the proportion of CD154+ T cells was similar in colon and small bowel, and interestingly, it was significantly reduced in colonic inflammatory bowel disease. Conclusions: Our findings suggested that modulation of CD40 expression by subepithelial macrophages and CD154 by lamina propria T cells is inversely modulated in the human gut. [source] | ||||||||||||||||||||||||||||