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MHC Class (mhc + class)

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Medical Sciences100%

Terms modified by MHC Class

  • mhc class i
  • mhc class i allele
  • mhc class i gene
    		•
  • mhc class i molecule
  • mhc class ii
  • mhc class ii expression
    		•
  • mhc class ii molecule
  • mhc class ii pathway

    • Selected Abstracts

    Microsomal triglyceride transfer protein regulates endogenous and exogenous antigen presentation by group,1 CD1 molecules

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2008
    Arthur Kaser
    Abstract Lipid antigens are presented to T cells by the non-polymorphic MHC class,I-related CD1 molecules. Microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum (ER)-resident chaperone that has been shown to lipidate the group,2 CD1 molecule CD1d and thus to regulate its function. We now report that MTP also regulates the function of group,1 CD1 molecules CD1a, CD1b, and CD1c. Pharmacological inhibition of MTP in monocyte-derived dendritic cells and lymphoblastoid B cell lines transfected with group,1 CD1 resulted in a substantial decrease in endogenous self lipid antigen presentation to several CD1-restricted T cell lines. Silencing MTP expression in CD1c-transfected HeLa cells similarly resulted in decreased self reactivity. Unexpectedly, inhibition of ER-resident MTP, which was confirmed by confocal microscopy, also markedly decreased presentation of exogenous, endosomally loaded, mycobacterial lipid antigens by CD1a and CD1c to T cells. Thus, these studies indicate that MTP, despite its ER localization, regulates endogenous as well as exogenous lipid antigen presentation, and suggest a broad role for MTP in the regulation of CD1 antigen presentation. [source]

    Dendritic cells derived from TBP-2-deficient mice are defective in inducing T cell responses

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2008
    Aoi 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]

    The role of ICOS in the development of CD4 T cell help and the reactivation of memory T cells

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007
    Simmi Mahajan
    Abstract We have addressed the role of the inducible costimulator (ICOS) in the development of T cell help for B cells and in the generation, survival and reactivation of memory CD4 T cells and B cells. We find that while T cell help for all antibody isotypes (including IgG2c) is impaired in ICOS knockout (ICOS-KO) mice, the IFN-, response is little affected, indicating a defect in helper function that is unrelated to cytokine production. In addition, the ICOS-negative T cells do not accumulate in B cell follicles. Secondary (memory), but not primary, clonal proliferation of antigen-specific B cells is impaired in ICOS-KO mice, as is the generation of secondary antibody-secreting cells. Analysis of endogenous CD4 memory cells in ICOS-KO mice, using MHC class,II tetramers, reveals normal primary clonal expansion, formation of memory clones and long-term (10,wk) survival of memory cells, but defective expansion upon reactivation in vivo. The data point to a role of ICOS in supporting secondary, memory and effector T cell responses, possibly by influencing cell survival. The data also highlight differences in ICOS dependency of endogenous T cell proliferation in vivo compared to that of adoptively transferred TCR-transgenic T cells. [source]

    Impairment of dendritic cell function by excretory-secretory products: A potential mechanism for nematode-induced immunosuppression

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007
    Mariela Segura
    Abstract To determine whether helminth-derived products modulate dendritic cell (DC) function, we investigated the effects of excretory-secretory products (ES) and adult worm homogenate (AWH) derived from the gastrointestinal nematode Heligmosomoides polygyrus (Hp) on murine bone marrow-derived DC (BMDC). Compared to the TLR9 ligand CpG, Hp-derived products alone failed to induce DC activation. ES, but not AWH, inhibited BMDC cytokine and chemokine production and co-stimulatory molecule expression (CD40, CD86 and MHC class,II) induced by TLR ligation. TLR ligand-independent, PMA-induced DC activation was unaffected by ES. Recipients of ES-treated BMDC pulsed with OVA had suppressed Ab responses in vivo, irrespective of the Th1 or Th2 isotype affiliation, compared to recipients of control OVA-pulsed BMDC. Importantly, suppression occurred even in the presence of the potent type,1 adjuvant CpG. In contrast to untreated OVA-pulsed BMDC, ES-treated BMDC pulsed with OVA had reduced co-stimulatory molecule and cytokine expression. CD4+CD25+Foxp3, T cells, which secreted high IL-10 levels, were generated in co-cultures of OT-II OVA-specific TCR-transgenic CD4+ T cells and ES-treated BMDC. These IL-10-secreting T cells suppressed effector CD4+ T cell proliferation and IFN-, production, the latter effect mediated by an IL-10-dependent mechanism. Together, these results demonstrate that nematode ES impaired DC function and suppressed both Th1 and Th2 adaptive immune responses possibly by inducing regulatory T cells. [source]

    IL-12 and IL-18 down-regulate B cell migration in an Ly49D-dependent manner

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007
    Gili Hart
    Abstract In order to complete their maturation and participate in the humoral immune response, immature B cells that leave the bone marrow are targeted to specific areas in the spleen, where they differentiate into mature cells. Previously, we showed that immature B cells actively down-regulate their integrin-mediated migration to LN or to sites of inflammation, enabling their targeting to the spleen. This inhibition is mediated by IFN-,, which is transcribed and secreted at low levels by these immature B cells; its expression is subsequently down-regulated following B cell maturation. The activating and inhibitory MHC class,I receptors, Ly49D and Ly49G2, regulate IFN-, secretion in B cells, preventing their migration to antigen-enriched sites and their premature encounter with an antigen, while enabling their entry into the LN when mature. In the present study, we elucidate the pathways by which the Ly49 receptors regulate IFN-, levels. We show that Ly49D stimulation triggers a signaling cascade that increases transcription of both IL-12B and IL-18; these, in turn, can interact with their specific receptors, which are expressed at elevated levels on immature B cells. Ligation of the IL-12B and IL-18 receptors induces the secretion of IFN-,, thereby regulating their cytoskeleton rearrangement and migration. [source]

    Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class,I invariant region

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2007
    Linda Wooldridge
    Abstract CD8+ cytotoxic T,lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class,I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the ,2,domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by,,50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 ,,chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens. [source]

    Pathologic expression of MHC class,II is driven by mitogen-activated protein kinases

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2007
    Isabelle Martins
    Abstract The class,II transactivator (CIITA) is the master regulator of MHC class,II molecules (MHC,II). In melanoma, the MHC,II are constitutively expressed due to an abnormal transcription of CIITA from its promoter,III (pIII), and requires the presence of a 1-kb enhancer located upstream from this latter. Since mitogen-activated protein kinases (MAPK) have been shown to be activated in most melanomas, we sought to analyze their possible involvement in CIITA expression. Using chemical inhibitors and dominant-negative constructs of MAPK-ERK kinase (Mek1) and MAPK-JNK, we evidenced the inhibition of MHC,II and CIITA expression in melanoma cell lines displaying activated MAPK. Transcriptional regulation by MAPK is known to involve the AP-1 transcription factor family. Sequence analysis revealed an AP-1-responsive motif in the enhancer of CIITA pIII at ,5954/,5947 from the site of transcription initiation. Its mutagenesis reduced CIITA expression four- to fivefold in melanoma cell lines and alleviated the effect of dominant-negative constructs of the MAPK pathway. Together, our findings demonstrate that MAPK-ERK and MAPK-JNK are regulators of CIITA transcription in melanoma, and pinpoint an AP-1-responsive site in the CIITA gene pIII. This should have considerable impact on our understanding of the physio-pathologic expression of MHC,II. [source]

    DNA vaccine encoding endosome-targeted human papillomavirus type,16 E7,protein generates CD4+ T cell-dependent protection

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2007
    Jean-Marc Brulet
    Abstract Human papillomavirus type,16 is commonly implicated in cervical cancers. The viral genome encodes potential targets like the oncoprotein,E7, expressed in transformed cells but thought to represent a poorly immunogenic antigen. We describe in this work a DNA-based vaccination protocol aimed at inducing an efficient anti-E7 immune response in vivo. Plasmids allowing the expression of the E7,protein in distinct cellular compartments were generated and assayed in an in vivo model of tumor growth. Our data demonstrate that mice vaccinated with a plasmid encoding for an E7,protein fused to a domain of the MHC class,II-associated invariant chain (IiE7) were protected against tumor challenge. Mice immunized against an ubiquitinated form of E7 (Ub(Ala)E7) failed to control tumor growth. Protection induced by IiE7 was correlated with the development of CD8+ CTL and required the presence of CD4+ cells. In vitro studies confirmed that the IiE7 fusion protein was expressed at high levels in the endosomal compartment of transfected cells, while the natural and the ubiquitin-modified form of E7 were mainly nuclear. The present study suggests that an efficient anti-tumor response can be induced in vivo by DNA constructs encoding for E7,protein forms localizing at the endosomal compartment. See accompanying commentary: http://dx.doi.org/10.1002/eji.200636233 [source]

    Structural requirements for initiation of cross-reactivity and CNS autoimmunity with a PLP139,151 mimic peptide derived from murine hepatitis virus

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2006
    Ludovic Croxford
    Abstract MS is an autoimmune CNS demyelinating disease in which infection appears to be an important pathogenic factor. Molecular mimicry, the cross-activation of autoreactive T cells by mimic peptides from infectious agents, is a possible explanation for infection-induced autoimmunity. Infection of mice with a non-pathogenic strain of Theiler's murine encephalomyelitis virus (TMEV) engineered to express an epitope from Haemophilus influenzae (HI) sharing 6/13 amino acids with the dominant proteolipid protein (PLP) epitope, PLP139,151, can induce CNS autoimmune disease. Here we demonstrate that another PLP139,151 mimic sequence derived from murine hepatitis virus (MHV) which shares only 3/13 amino acids with PLP139,151 can also induce CNS autoimmune disease, but only when delivered by genetically engineered TMEV, not by immunization with the MHV peptide. Further, we demonstrate the importance of proline at the secondary MHC class,II contact residue for effective cross-reactivity, as addition of this amino acid to the native MHV sequence increases its ability to cross-activate PLP139,151 -specific autoreactive T cells, while substitution of proline in the HI mimic peptide has the opposite effect. This study describes a structural requirement for potential PLP139,151 mimic peptides, and provides further evidence for infection-induced molecular mimicry in the pathogenesis of autoimmune disease. [source]

    Breakpoints in immunoregulation required for Th1 cells to induce diabetes

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006
    Margaret 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]

    Revisiting the specificity of the MHC class,II transactivator CIITA in vivo

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2006

    Abstract CIITA is a master regulatory factor for the expression of MHC class,II (MHC-II) and accessory genes involved in Ag presentation. It has recently been suggested that CIITA also regulates numerous other genes having diverse functions within and outside the immune system. To determine whether these genes are indeed relevant targets of CIITA in vivo, we studied their expression in CIITA-transgenic and CIITA-deficient mice. In contrast to the decisive control of MHC-II and related genes by CIITA, nine putative non-MHC target genes (Eif3s2, Kpna6, Tap1, Yars, Col1a2, Ctse, Ptprr, Tnfsf6 and Plxna1) were found to be CIITA independent in all cell types examined. Two other target genes, encoding IL-4 and IFN-,, were indeed found to be up- and down-regulated, respectively, in CIITA-transgenic CD4+ T,cells. However, there was no correlation between MHC-II expression and this Th2 bias at the level of individual transgenic T,cells, indicating an indirect control by CIITA. These results show that MHC-II-restricted Ag presentation, and its indirect influences on T,cells, remains the only pathway under direct control by CIITA in vivo. They also imply that precisely regulated MHC-II expression is essential for maintaining a proper Th1-Th2 balance. [source]

    Modulation of dendritic cell phenotype and functionin an in vitro model of the intestinal epithelium

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2006
    Matt 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]

    Immediate antigen-specific effector functions byTCR-transgenic CD8+ NKT cells

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2006
    Gerhard Wingender
    Abstract Only recently have natural antigens for CD1d-dependent, invariant V,14+ natural killer T (iNKT) cells been identified. Similar data for CD1d-independent and CD8+ NKT cell populations are still missing. Here, we show that the MHC class,I-restricted CD8+ TCR-transgenic mouse lines OT-I, P14 and H-Y contain a significant proportion of transgenic CD8+ NK1.1+ T,cells. In liver, most of NK1.1+ T,cells express CD8,, homodimers. Transgenic NKT cells did not bind invariant V,14-to-J,18 TCR rearrangement (V,14i)-specific CD1d/,-galactosylceramide tetramers and the frequency of iNKT cells was severely reduced. The activated cell surface phenotype and the distribution of transgenic NKT cells in vivo were similar to that reported for iNKT cells. The OT-I and P14 CD8+ NKT cells recognized their cognate antigen in the context of H2-Kb and produced cytokines shortly after TCR stimulation. Importantly, transgenic NKT cells exerted immediate antigen-specific cytotoxicity in vitro and in vivo. Our results demonstrate the presence of transgenic CD8+ NKT cells in MHC class,I-restricted TCR-transgenic animals, which are endowed with rapid antigen-specific effector functions. These data imply that experiments studying naive T,cell function in TCR-transgenic animals should be interpreted with caution, and that such animals could be utilized for studying CD8+ NKT cell function in an antigen-specific manner. [source]

    Site-specific expression of CD11b and SIRP, (CD172a) on dendritic cells: implications for their migration patterns in the gut immune system

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2005
    Diane 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]

    The MHC class,II transactivator (CIITA) mRNA stability is critical for the HLA class,II gene expression in myelomonocytic cells

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2005
    Andrea De Lerma Barbaro
    Abstract The human promyelocytic U937 cells express detectable levels of MHC class,II (MHC-II) molecules. Treatment with 12-o- - tetradecanoyl phorbol 13-acetate (TPA), inducing macrophage-like differentiation, produces a dramatic decrease of MHC-II expression as result of down-modulation of the activation of immune response gene,1 (AIR-1)-encoded MHC-II transactivator (CIITA). This event is specific, as MHC class,I remains unaffected. Similar results are observed with U937 cells expressing an exogenous full-length CIITA. Molecular studies demonstrate that TPA treatment affects the stability of CIITA mRNA rather than CIITA transcription. Importantly, cis -acting elements within the distal 650,bp of the 1035-bp 3,,untranslated region (3,UTR, nucleotides 3509,4543) are associated to transcript instability. Transcription inhibitors actinomycin,D and 5,6-dichlororibofuranosyl benzimidazole, and the translation inhibitor cycloheximide significantly rescue the accumulation of CIITA mRNA in TPA-treated cells. A similar effect is also observed after treatment with staurosporine and the PKC-specific inhibitor GF109203X. The instability of CIITA mRNA produced by TPA in U937 cells is not seen in B,cells. These results demonstrate the presence of an additional level of control of MHC-II expression in the macrophage cell lineage depending upon the control of CIITA mRNA stability, most likely mediated by differentiation-induced, 3,UTR-interacting factors which require kinase activity for their destabilizing function. [source]

    Intraocular injection of tamoxifen-loaded nanoparticles: a new treatment of experimental autoimmune uveoretinitis

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004
    Yvonne de Kozak
    Abstract In this study, we tested the efficiency of an intravitreal injection of tamoxifen, a non-steroidal estrogen receptor modulator, in retinal soluble antigen (S-Ag)-induced experimental autoimmune uveoretinitis (EAU). To increase the bioavailability of tamoxifen, we incorporated tamoxifen into polyethylene glycol (PEG)-coated nanoparticles (NP-PEG-TAM). The localization of the nanoparticles within the eye was investigated using fluorescent-labeled PEG-coated nanoparticles after injection into the vitreous cavity of rats with EAU. Some nanoparticles were distributed extracellularly throughout the ocular tissues, others were concentrated in resident ocular cells and in infiltrating macrophages. Whereas the injection of free tamoxifen did not alter the course of EAU, injection of NP-PEG-TAM performed 1,2,days before the expected onset of the disease in controls resulted in significant inhibition of EAU. NP-PEG-TAM injection significantly reduced EAU compared to injection of NP-PEG-TAM with 17,-estradiol (E2), suggesting that tamoxifen is acting as a partial antagonist to E2. Diminished infiltration by MHC class,II+ inflammatory cells and low expression of TNF-,, IL-1,, and RANTES mRNA were noted in eyes of NP-PEG-TAM-treated rats. Intravitreal injection of NP-PEG-TAM decreased S-Ag lymphocyte proliferation, IFN-, production by inguinal lymph node cells, and specific delayed-type hypersensitivity indicative of a reduced Th1-type response. It increased the anti-S-Ag IgG1 isotype indicating an antibody class switch to Th2 response. These data suggest that NP-PEG-TAM inhibition of EAU could result from a form of immune deviation. Tamoxifen-loaded nanoparticles may represent a new option for the treatment of experimental uveitis. [source]

    Anti-tumor MHC class,Ia-unrestricted CD8 T,cell cytotoxicity elicited by the heat shock protein gp96

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2004
    Ana Goyos
    Abstract In Xenopus as in mammals, gp96 stimulates MHC-restricted cellular immunity against chaperoned minor histocompatibility (H) antigens (Ag). In adult Xenopus, gp96 also elicits peptide-specific effectors against MHC class,Ia-negative 15/0 tumors. To determine whether gp96 can generate functionally heterogeneous CD8+ effectors (CTL that kill MHC class,Ia+ minor,H-Ag-disparate lymphoblasts and MHC class,Ia, tumor targets), LG-6 isogenetic frogs were immunized with gp96 purified either from MHC-identical but minor,H-Ag-disparate LG-15 normal tissues or from the MHC class,Ia-negative 15/0 tumor line (derived from LG-15 frogs). LG-15 normal liver-derived gp96 did not induce detectable CD8+in vitro killing against 15/0 tumor cells. However, 15/0-derived gp96 did induce killing against both MHC class,Ia+ LG-15 lymphoblasts and the MHC class,Ia, 15/0 tumor, but not against another MHC class,Ia, tumor (B3B7) or against LG-6 lymphoblasts. Tumor killing was better when 15/0 rather than normal LG-15 irradiated stimulators were used, but in vitro stimulation without prior in vivo immunization was ineffective. These data suggest that (1),15/0-derived gp96 chaperones minor,H-Ag shared with normal LG-15 lymphocytes and elicits MHC-restricted CTL, and (2),15/0-derived gp96, but not normal liver-derived gp96, generates CD8+ effectors that kill 15/0 tumor cells in the absence of MHC class,Ia expression. [source]

    Treatment of neonatal mice with Flt3 ligand leads to changes in dendritic cell subpopulations associated with enhanced IL-12 and IFN-, production

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2004
    Sabine Vollstedt
    Abstract Treatment with the hematopoietic growth factor Flt3 ligand (FL) increases DC numbers in neonatal mice and enhances their resistance against intracellular pathogens. Flow cytometric analysis showed the presence of conventional DC (cDC) and plasmacytoid pre-DC (pDC) in neonatal spleens from untreated and FL-treated mice. CD8, and MHC class,II expression on cDC and pDC was higher on DC from FL-treated mice than on DC from control littermates. After FL treatment, two additional subpopulations of DC-lineage cells were found that were able to produce IL-12 and IFN-,. The IL-12 production of cDC from FL-treated animals was more than 50-fold increased and their ability to stimulate T,cell proliferation was also increased. We conclude that the enhanced resistance against intracellular pathogens was due to increased numbers of DC-lineage cells and their increased ability to produce the essential cytokines. [source]

    Comparative genomics of the Mill family: a rapidly evolving MHC class,I gene family

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2004
    Yutaka Watanabe
    Abstract Mill (MHC class,I-like located near the leukocyte receptor complex) is a novel family of class,I genes identified in mice that is most closely related to the human MICA/B family. In the present study, we isolated Mill cDNA from rats and carried out a comparative genomic analysis. Rats have two Mill genes orthologous to mouse Mill1 and Mill2 near the leukocyte receptor complex, with expression patterns similar to those of their mouse counterparts. Interspecies sequence comparison indicates that Mill is one of the most rapidly evolving class,I gene families and that non-synonymous substitutions occur more frequently than synonymous substitutions in its ,,1 domain, implicating the involvement of Mill in immune defenses. Interestingly, the ,,2 domain of rat Mill2 contains a premature stop codon in many inbred strains, indicating that Mill2 is not essential for survival. A computer search of the database identified a horse Mill -like expressed sequence tag, indicating that Mill emerged before the radiation of mammals. Hence, the failure to find Mill in human indicates strongly that it was lost from the human lineage. Our present work provides convincing evidence that Mill is akin to the MICA/B family, yet constitutes a distinctgene family. [source]

    Demonstration of strong enterobacterial reactivity of CD4+CD25, T,cells from conventional and germ-free mice which is counter-regulated by CD4+CD25+ T,cells

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2004
    Monika Gad
    Abstract Unfractionated CD4+ T,cells from the gut-associated lymphoid tissue (GALT) and peripheral lymph nodes are unresponsive when exposed to enterobacterial antigens in vitro. Under similar conditions, CD4+ T,cells depleted in vivo or in vitro of CD4+CD25+ T,cells proliferate extensively. The CD4+CD25, T,cell reactivity depends on MHC class,II presentation, specific TCR stimulation, CD4 ligation, and antigen processing by antigen-presenting cells. The CD4+CD25, T,cells respond to autologousand heterologous enterobacterial antigens, but not to antigens from the feces of germ-free mice. Surprisingly, CD4+CD25, T,cells obtained from the GALT of germ-free mice also proliferate when exposed to enterobacterial antigens, and adding back the conventional or germ-free CD4+CD25+ T,cells to the enteroantigen-stimulated CD4+CD25, T,cells abolishes proliferation. As judged from carboxyfluorescein diacetate succinimidyl ester-labeling experiments, 4,5% of the CD4+CD25, T,cells respond to enteroantigen. The data show for the first time that CD4+CD25, T,cells with reactivity towards the enterobacterial flora and regulatory CD4+CD25+ T,cells are present in both conventional and germ-free mice. The data suggest that a significant proportion of the peripheral pool of CD4+CD25, T,cells express anti-enterobacterial reactivity, which, due to the presence of regulatory CD4+CD25+ T,cells, is kept in a quiescent state. [source]

    A CIITA-independent pathway that promotes expression of endogenous rather than exogenous peptides in immune-privileged sites

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2004
    Carolina
    Abstract A CIITA-independent pathway of MHC class II expression has been found in the eye and the brain, both immune-privileged sites. Although corneal endothelial cells were unable to express MHC class,II in response to IFN-, alone, these cells readily expressed MHC class,II molecules via a CIITA-independent pathway when triggered by simultaneous exposure to IFN-, and TNF-,. CIITA-independent expression of MHCclass,II molecules enabled corneal endothelial cells to present cytosolic, but not endosomal, ovalbumin (OVA) to OVA-primed T,cells. To determine whether CIITA-independentexpression of MHC class,II is relevant in vivo, minor,H-only-incompatible corneal allografts prepared from CIITA knockout (KO) mice, MHC class,II KO mice or wild-type donors were placed ineyes of normal mice. Cornea allografts from wild-type and CIITA KO mice suffered similar rejection fates, whereas far fewer class,II-deficient corneas were rejected. In addition, MHC class,II-bearing macrophages were observed in cuprizone-induced inflammatory and demyelinating brain lesions of CIITA KO mice. We conclude that class,II expression via the CIITA-independent pathway enhances the vulnerability to rejection of corneal grafts expressing minor antigens. The potential relevance of CIITA-independent MHC class,II expression at immune-privileged sites is discussed in relation to tolerance to strong autoantigens. [source]

    Uncompromised generation of a specific H-2DM-dependent peptide-MHC class,II complex from exogenous antigen in Leishmania mexicana -infected dendritic cells

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2003
    Clare
    Abstract Leishmania infection inhibits the capacity of macrophages (M,) to present antigens to CD4+ T cells. Relocation of MHC class,II and H-2DM to the parasitophorous vacuole (PV) and their subsequent degradation by the parasite may contribute to this defect. Dendritic cells (DC) are critical for initiation of primary T cell responses. DC can process Leishmania antigen and elicit Leishmania -specific T cells, but it is unknown whether exposure to Leishmania impairs this capacity. In particular, it is not clear whether DC containing live parasites efficiently process and present antigens. We investigated the ability of mouse bone marrow-derived DC infected with L. mexicana to generate pigeon cytochrome,c (PCC) peptide-MHC class II complexes, using the mAb D4, which recognizes PCC89,104 H-2Ek, and the PCC-specific T cell hybridoma 2B4. We show that H-2DM-dependent complex generation is not compromised by infection and that complexes are fully recognized by specific T cells. We further show that in contrast to infected M,, in infected DC cytoplasmic H-2DM is not down-regulated and not relocated to the parasite-containing vacuole. This observation may explain the continued ability of infected DC to present PCC, and also indicates differences in the habitat of these intracellular parasites in DC compared to M,. [source]

    Incomplete effector/memory differentiation of antigen-primed CD8+ T,cells in gene gun DNA-vaccinated mice

    EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2003
    Christina Bartholdy
    Abstract DNA vaccination is an efficient way to induce CD8+ T,cell memory, but it is still unclear to what extent such memory responses afford protection in vivo. To study this, we induced CD8+ memory responses directed towards defined viral epitopes, using DNA vaccines encoding immunodominant MHC class,I-restricted epitopes of lymphocytic choriomeningitis virus covalently linked to ,2-microglobulin. This vaccine construct primed for a stronger recall response than did a more conventional minigene construct. Despite this, vaccinated mice were only protected against systemic infection whereas protection against the consequences of peripheral challenge was limited. Phenotypic analysis revealed that DNA vaccine-primed CD8+ T,cells in uninfected mice differed from virus-primed CD8+ T,cells particularly regarding expression of very-late antigen (VLA)-4, an adhesion molecule important for targeting T,cells to inflammatory sites. Thus, our DNA vaccine induces a long-lived memory CD8+ T,cell population that provides efficient protection against high-dose systemic infection. However, viral replication in solid non-lymphoid organs is not curtailed sufficiently fast to prevent significant virus-induced inflammation. Our results suggest that this is due to qualitative limitations of the primed CD8+ T,cells. [source]

    Ocular toxoplasmosis: in the storm of the eye

    PARASITE IMMUNOLOGY, Issue 12 2006
    L. A. JONES
    SUMMARY Ocular toxoplasmosis (OT) can occur in the children of mothers infected with Toxoplasma gondii during pregnancy. It is not limited to the congenitally infected, but can also occur following adult-acquired infection or as a result of disease reactivation in immune-compromised and pregnant individuals. Many aspects of immune privilege in the eye, including constitutive TGF-, expression and reduced MHC class 1 expression, would appear at first to favour parasite survival. Conversely, many of the mechanisms that control parasite multiplication in other anatomical sites, such as nitric oxide expression, IFN-, and TNF-,, are known to disrupt immune privilege and are associated with ocular damage. Taking into account the opposing needs of limiting parasite multiplication and minimizing tissue destruction we review the pathogenesis of OT in the murine model. [source]