Journal articles on the topic 'Ova-transgenic'
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1
Dillon, S. R., S. C. Jameson, and P. J. Fink. "V beta 5+ T cell receptors skew toward OVA+H-2Kb recognition." Journal of Immunology 152, no. 4 (February 15, 1994): 1790–801. http://dx.doi.org/10.4049/jimmunol.152.4.1790.
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Abstract T cells recognize a complex of peptide Ag bound within the groove of MHC-encoded molecules. Although many studies have attempted to correlate TCR gene expression with specificity for particular Ag/MHC combinations, it is still not clear exactly how the TCR physically interacts with its cognate ligand. We have analyzed transgenic mice that carry a rearranged gene encoding a V beta 5.2+ TCR beta-chain derived from the CD8+ CTL clone B3, which is specific for chicken OVA+H-2Kb. Surprisingly, we have found that peripheral lymphocytes isolated from naïve V beta 5.2 transgenic mice can generate a strong primary anti-OVA CTL response when stimulated in vitro with OVA+H-2b, whereas generation of even a weak anti-OVA response from nontransgenic littermates requires in vivo priming. This response is Ag specific, because the transgenic mice are unable to respond with or without priming to vesicular stomatitis virus, which contains a dominant epitope presented in the context of H-2Kb. The precursor frequency of OVA-specific CTL in unprimed V beta 5.2 transgenic mice is approximately 30-fold higher than that in nontransgenic littermate controls. Reverse transcription-PCR analyses demonstrate that OVA-specific CTL lines derived from unprimed V beta 5.2 transgenic mice express a variety of TCR V alpha elements, indicating that the transgenic anti-OVA response is not solely due to the reconstitution of the original B3 TCR. In fact, our data suggest that even a nontransgenic V beta 5+ TCR is intrinsically OVA specific. First, five separate OVA-specific oligoclonal CTL lines derived from individual nontransgenic mice demonstrate dramatic skewing toward expression of V beta 5.1+ or V beta 5.2+ TCR over the course of several in vitro stimulations. Second, sorting for V beta 5+CD8+ nontransgenic cells enriches for OVA-specific CTL. However, peptide antagonism experiments using mutant forms of the Kb-restricted OVA peptide reveal distinct differences between the recognition patterns of two individual OVA-specific CTL lines derived from unprimed V beta 5.2 transgenic mice. These experiments support the notion that a discrete portion of the responding TCR can heavily influence but not necessarily be solely sufficient for the recognition of a peptide Ag presented in the cleft of an MHC-encoded molecule.
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Larsen, Gary L., Carl W. White, Katsuyuki Takeda, Joan E. Loader, Dee Dee H. Nguyen, Anthony Joetham, Yoram Groner, and Erwin W. Gelfand. "Mice that overexpress Cu/Zn superoxide dismutase are resistant to allergen-induced changes in airway control." American Journal of Physiology-Lung Cellular and Molecular Physiology 279, no. 2 (August 1, 2000): L350—L359. http://dx.doi.org/10.1152/ajplung.2000.279.2.l350.
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Within the respiratory epithelium of asthmatic patients, copper/zinc-containing superoxide dismutase (Cu/Zn SOD) is decreased. To address the hypothesis that lung Cu/Zn SOD protects against allergen-induced injury, wild-type and transgenic mice that overexpress human Cu/Zn SOD were either passively sensitized to ovalbumin (OVA) or actively sensitized by repeated airway exposure to OVA. Controls included nonsensitized wild-type and transgenic mice given intravenous saline or airway exposure to saline. After aerosol challenge to saline or OVA, segments of tracheal smooth muscle were obtained for in vitro analysis of neural control. In response to electrical field stimulation, wild-type sensitized mice challenged with OVA had significant increases in cholinergic reactivity. Conversely, sensitized transgenic mice challenged with OVA were resistant to changes in neural control. Stimulation of tracheal smooth muscle to elicit acetylcholine release showed that passively sensitized wild-type but not transgenic mice released more acetylcholine after OVA challenge. Function of the M2 muscarinic autoreceptor was preserved in transgenic mice. These results demonstrate that murine airways with elevated Cu/Zn SOD were resistant to allergen-induced changes in neural control.
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Garulli, Bruno, Giuseppina Di Mario, Ester Sciaraffia, Yoshihiro Kawaoka, and Maria R. Castrucci. "Immunogenicity of a Recombinant Influenza Virus Bearing Both the CD4+ and CD8+ T Cell Epitopes of Ovalbumin." Journal of Biomedicine and Biotechnology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/497364.
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Recombinant influenza viruses that bear the single immunodominant CD8+ T cell epitopeOVA257−264or the CD4+ T cell epitopeOVA323−339of the model antigen ovalbumin (OVA) have been useful tools in immunology. Here, we generated a recombinant influenza virus,WSN-OVAI/II, that bears both OVA-specific CD8+ and CD4+ epitopes on its hemagglutinin molecule. Live and heat-inactivatedWSN-OVAI/IIviruses were efficiently presented by dendritic cellsin vitroto OT-I TCR transgenic CD8+ T cells and OT-II TCR transgenic CD4+ T cells.In vivo,WSN-OVAI/IIvirus was attenuated in virulence, highly immunogenic, and protected mice from B16-OVA tumor challenge in a prophylactic model of vaccination. Thus,WSN-OVAI/IIvirus represents an additional tool, along with OVA TCR transgenic mice, for further studies on T cell responses and may be of value in vaccine design.
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Pepper, Marion, Florence Dzierszinski, Amy Crawford, Christopher A. Hunter, and David Roos. "Development of a System To Study CD4+-T-Cell Responses to Transgenic Ovalbumin-Expressing Toxoplasma gondii during Toxoplasmosis." Infection and Immunity 72, no. 12 (December 2004): 7240–46. http://dx.doi.org/10.1128/iai.72.12.7240-7246.2004.
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ABSTRACT The study of the immune response to Toxoplasma gondii has provided numerous insights into the role of T cells in resistance to intracellular infections. However, the complexity of this eukaryote pathogen has made it difficult to characterize immunodominant epitopes that would allow the identification of T cells with a known specificity for parasite antigens. As a consequence, analysis of T-cell responses to T. gondii has been based on characterization of the percentage of T cells that express an activated phenotype during infection and on the ability of these cells to produce cytokines in response to complex mixtures of parasite antigens. In order to study specific CD4+ T cells responses to T. gondii, recombinant parasites that express a truncated ovalbumin (OVA) protein, in either a cytosolic or a secreted form, were engineered. In vitro and in vivo studies reveal that transgenic parasites expressing secreted OVA are able to stimulate T-cell receptor-transgenic OVA-specific CD4+ T cells to proliferate, express an activated phenotype, and produce gamma interferon (IFN-γ). Furthermore, the adoptive transfer of OVA-specific T cells into IFN-γ−/− mice provided enhanced protection against infection with the OVA-transgenic (but not parental) parasites. Together, these studies establish the utility of this transgenic system to study CD4+-T-cell responses during toxoplasmosis.
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Degermann, S., E. Pria, and L. Adorini. "Soluble protein but not peptide administration diverts the immune response of a clonal CD4+ T cell population to the T helper 2 cell pathway." Journal of Immunology 157, no. 8 (October 15, 1996): 3260–69. http://dx.doi.org/10.4049/jimmunol.157.8.3260.
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Abstract BALB/c mice immunized with protein Ags such as OVA in adjuvant mount a Th1-type response. Inhibition of Th1 and development of Th2 cells can be induced by pretreating BALB/c mice with soluble OVA before priming. To investigate some aspects of this immune deviation in vivo, naive TCR transgenic T cells specific for the chicken OVA peptide 323-339 presented by I-A(d) molecules were adoptively transferred into normal BALB/c mice. The frequency and fate of the transferred T cells can be followed with an anti-clonotypic Ab. In response to priming with OVA in CFA, the transferred transgenic T cells expand and differentiate into Th1 cells producing IL-2 and IFN-gamma. If recipient mice are injected with soluble OVA before priming, the frequency of transgenic T cells is not affected, but their expansion in response to Ag priming is inhibited. Yet, the fewer transgenic T cells recovered are not anergic, they proliferate as control cells when restimulated in vitro by plate-bound anticlonotypic Ab or by Ag. Analysis of Th phenotype indicates that pretreatment with soluble OVA has suppressed Th1 cell differentiation in favor of the generation of Th2 cells producing IL-4 and IL-5. Pretreatment with soluble peptide 323-339 also inhibits Th1 cell development, but fails to induce Th2 cell differentiation. Thus, pretreatment with soluble protein Ag or with synthetic peptide inhibits Th1 cell development, but only protein, not peptide, administration can deviate the in vivo response of a clonal T cell population from the Th1 to the Th2 pathway.
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Kurts, Christian, Isis Ludwig-Portugall, Emma E. Hamilton-Williams, Catherine Gottschalk, and Janine Gotot. "Antigen-specific suppression of non-lymphoid tissue auto-antibody production by CD25+ FoxP3+ regulatory T cells (89.22)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 89.22. http://dx.doi.org/10.4049/jimmunol.182.supp.89.22.
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Abstract To study how peripheral B cell tolerance against non-lymphoid tissue autoantigens is maintained, we generated transgenic RIP-OVA/HEL (ROH) mice expressing the model antigens, OVA and HEL, in pancreatic islet beta cells. Immunization with OVA/HEL/aluminiumhydroxide induced IgG auto-Ab titers that were much lower than in non-transgenic controls. Depletion of CD25+ cells during immunization completely restored auto-Ab production but did not affect titers against foreign antigens, indicating regulatory tolerance. Purified CD25+ FoxP3+ CD4+ T cells from ROH mice transferred B cell suppression into non-transgenic recipients. CD25+ cells also suppressed naïve transgenic HEL-specific B cells adoptively transferred into ROH mice, confirming peripheral B cell tolerance. B cell suppression mechanistically involved inhibiting the proliferation of autoreactive B cells, inducing their apoptosis after immunization with autoantigen, suppressing antibody secretion per B cell and downregulating IgMa and MHC II B cell surface expression in the autoantigen-draining lymph node. We conclude that CD25+ FoxP3+ regulatory T cells were necessary and sufficient to specifically suppress auto-Ab production against pancreatic islet cell antigens.
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Leibo, S. P., Francesco J. De Mayo, and Bert O'Malley. "Production of transgenic mice from cryopreserved fertilized ova." Molecular Reproduction and Development 30, no. 4 (December 1991): 313–19. http://dx.doi.org/10.1002/mrd.1080300405.
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Ingulli, Elizabeth, Anna Mondino, Alexander Khoruts, and Marc K. Jenkins. "In Vivo Detection of Dendritic Cell Antigen Presentation to CD4+ T Cells." Journal of Experimental Medicine 185, no. 12 (June 16, 1997): 2133–41. http://dx.doi.org/10.1084/jem.185.12.2133.
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Although lymphoid dendritic cells (DC) are thought to play an essential role in T cell activation, the initial physical interaction between antigen-bearing DC and antigen-specific T cells has never been directly observed in vivo under conditions where the specificity of the responding T cells for the relevant antigen could be unambiguously assessed. We used confocal microscopy to track the in vivo location of fluorescent dye-labeled DC and naive TCR transgenic CD4+ T cells specific for an OVA peptide–I-Ad complex after adoptive transfer into syngeneic recipients. DC that were not exposed to the OVA peptide, homed to the paracortical regions of the lymph nodes but did not interact with the OVA peptide-specific T cells. In contrast, the OVA peptide-specific T cells formed large clusters around paracortical DC that were pulsed in vitro with the OVA peptide before injection. Interactions were also observed between paracortical DC of the recipient and OVA peptide-specific T cells after administration of intact OVA. Injection of OVA peptide-pulsed DC caused the specific T cells to produce IL-2 in vivo, proliferate, and differentiate into effector cells capable of causing a delayed-type hypersensitivity reaction. Surprisingly, by 48 h after injection, OVA peptide-pulsed, but not unpulsed DC disappeared from the lymph nodes of mice that contained the transferred TCR transgenic population. These results demonstrate that antigen-bearing DC directly interact with naive antigen-specific T cells within the T cell–rich regions of lymph nodes. This interaction results in T cell activation and disappearance of the DC.
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Bertholet, Sylvie, Alain Debrabant, Farhat Afrin, Elisabeth Caler, Susana Mendez, Khaled S. Tabbara, Yasmine Belkaid, and David L. Sacks. "Antigen Requirements for Efficient Priming of CD8+ T Cells by Leishmania major-Infected Dendritic Cells." Infection and Immunity 73, no. 10 (October 2005): 6620–28. http://dx.doi.org/10.1128/iai.73.10.6620-6628.2005.
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ABSTRACT CD4+ and CD8+ T-cell responses have been shown to be critical for the development and maintenance of acquired resistance to infections with the protozoan parasite Leishmania major. Monitoring the development of immunodominant or clonally restricted T-cell subsets in response to infection has been difficult, however, due to the paucity of known epitopes. We have analyzed the potential of L. major transgenic parasites, expressing the model antigen ovalbumin (OVA), to be presented by antigen-presenting cells to OVA-specific OT-II CD4+ or OT-I CD8+ T cells. Truncated OVA was expressed in L. major as part of a secreted or nonsecreted chimeric protein with L. donovani 3′ nucleotidase (NT-OVA). Dendritic cells (DC) but not macrophages infected with L. major that secreted NT-OVA could prime OT-I T cells to proliferate and release gamma interferon. A diminished T-cell response was observed when DC were infected with parasites expressing nonsecreted NT-OVA or with heat-killed parasites. Inoculation of mice with transgenic parasites elicited the proliferation of adoptively transferred OT-I T cells and their recruitment to the site of infection in the skin. Together, these results demonstrate the possibility of targeting heterologous antigens to specific cellular compartments in L. major and suggest that proteins secreted or released by L. major in infected DC are a major source of peptides for the generation of parasite-specific CD8+ T cells. The ability of L. major transgenic parasites to activate OT-I CD8+ T cells in vivo will permit the analysis of parasite-driven T-cell expansion, differentiation, and recruitment at the clonal level.
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Sukumar, Madhusudhanan, Andrea Wilke, Eva Jaeger, Josef Mautner, Joachim Ellwart, Hans-Jochem Kolb, Georg W. Bornkamm, and Armin Gerbitz. "Host Interferon gamma Production and STAT-1 Signalling Is Crucial for Minor Antigen Mediated Rejection of High Grade Lymphoma." Blood 110, no. 11 (November 16, 2007): 2175. http://dx.doi.org/10.1182/blood.v110.11.2175.2175.
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Abstract To date mechanisms of T-cell mediated immunity and immune-escape in high grade lymphomas are poorly understood. Using a transgenic mouse lymphoma model, where the proto-oncogene c-myc is driven in parts of the immunoglobulin lambda locus representing a t(8;22) translocation as found in Burkitt’s lymphoma, we developed a syngeneic model to investigate the anti-lymphoma activity of lymphoma specific T-cells. By retroviral transduction of a lymphoma specific antigen (chicken ovalbumin-IRES-GFP vector) into primary cell lines from c-myc transgenic lymphomas we established a model that would allow us to investigate the contribution of interferon gamma signalling in rejection of high grade lymphoma. All lymphomas established displayed low MHC class I and II levels on the surface when compared to wildtype B-cells. This expression could be enhanced by treatment with interferon gamma (100U/ml) up to 10 fold. When retrovirally transduced lymphoma cells were injected into wildtype or GFP transgenic C57BL/6 recipients, animals displayed a significant delay in lymphoma growth compared to IRES-GFP transduced control cell lines. 50% of the recipient mice rejected OVA containing lymphomas whereas we observed a 100% lymphoma growth of IRES-GFP transduced lymphomas in GFP transgenic recipients. Developing OVA containing lymphomas displayed a loss of GFP expression indicating a selection for non transduced cells. In spleens from mice successfully rejecting OVA-containing lymphomas we found up to 1.5% (±0.12%) SIINFEKL specific T-cells. To gain mechanistic insights of lymphoma rejection, we transferred OVA transduced lymphoma cells to Stat1−/− and IFNg−/− recipients. Lack of STAT1−/− on the recipient side or inability to secrete interferon gamma was associated with fast lymphoma progression and was not different when compared to IRES-GFP transduced cell lines injected into GFP transgenic hosts. Although we found 1.6% (±0.52%) SIINFEKL T cells in spleens of lymphoma bearing STAT1−/− animals, interferon gamma production was significantly decreased. We could also show that in wild type recipients, OVA containing lymphomas displayed high MHC class I and II expression which is completely absent in lymphomas from Stat1−/− recipients. Our results suggest that rejection of high grade lymphoma by a specific minor antigen is possible and Stat1 signaling and interferon gamma production by the host is crucial for lymphoma rejection.
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Kim, Ronald, Wujiang Liu, Xiaohong Chen, Karl J. Kreder, and Yi Luo. "Intravesical Dimethyl Sulfoxide Inhibits Acute and Chronic Bladder Inflammation in Transgenic Experimental Autoimmune Cystitis Models." Journal of Biomedicine and Biotechnology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/937061.
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New animal models are greatly needed in interstitial cystitis/painful bladder syndrome (IC/PBS) research. We recently developed a novel transgenic cystitis model (URO-OVA mice) that mimics certain key aspects of IC/PBS pathophysiology. This paper aimed to determine whether URO-OVA cystitis model was responsive to intravesical dimethyl sulfoxide (DMSO) and if so identify the mechanisms of DMSO action. URO-OVA mice developed acute cystitis upon adoptive transfer of OVA-specific OT-I splenocytes. Compared to PBS-treated bladders, the bladders treated with 50% DMSO exhibited markedly reduced bladder histopathology and expression of various inflammatory factor mRNAs. Intravesical DMSO treatment also effectively inhibited bladder inflammation in a spontaneous chronic cystitis model (URO-OVA/OT-I mice). Studies further revealed that DMSO could impair effector T cells in a dose-dependent manner in vitro. Taken together, our results suggest that intravesical DMSO improves the bladder histopathology of IC/PBS patients because of its ability to interfere with multiple inflammatory and bladder cell types.
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Blazar, B. R., M. K. Jenkins, P. A. Taylor, J. White, A. Panoskaltsis-Mortari, R. Korngold, and D. A. Vallera. "Anti-CD3 epsilon F(ab')2 fragments inhibit T cell expansion in vivo during graft-versus-host disease or the primary immune response to nominal antigen." Journal of Immunology 159, no. 12 (December 15, 1997): 5821–33. http://dx.doi.org/10.4049/jimmunol.159.12.5821.
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Abstract This study was undertaken to distinguish between several mechanisms responsible for graft-vs-host disease (GVHD) protection in anti-CD3epsilonF(ab')2 fragment (Fr)-treated recipients: TCR down-modulation, deletion, failure of expansion, or anergy induction. To quantify alloreactive T cell expansion and function, thoracic duct lymphocytes (TDL) were analyzed. Sixfold fewer donor TDL T cells were recoverable from anti-CD3epsilonF(ab')2 Fr as compared with irrelevant F(ab')2 Fr-treated recipients at the time of peak T cell expansion in vivo. Kinetic analysis revealed that donor T cell expansion was inhibited and not simply delayed by anti-CD3epsilonF(ab')2 Fr. Similar proportions of TDL T cells in irrelevant and anti-CD3epsilonF(ab')2 Fr were undergoing apoptosis. Although TCR modulation was observed, donor TDL T cells had intact anti-host alloresponses as compared with irrelevant F(ab')2 Fr-treated recipients. Because donor CD4+ T cells are primarily responsible for GVHD in this model, an adoptive transfer system was used in which the function and kinetics of expansion of OVA-specific CD4+ TCR transgenic cells could be physically tracked. Relevant Fr severely blunted CD4+ TCR transgenic T cell clonal expansion after OVA administration. Nonviable transgenic and nontransgenic T cells were proportionally similar in OVA-pulsed recipients, regardless of whether relevant or irrelevant F(ab')2 Fr were given. After discontinuing Fr, transgenic T cells were found to have intact in vitro OVA-specific responses. Our current and previous results suggest that reduced donor T cell expansion and T cell depletion both contribute to GVHD protection by anti-CD3epsilonF(ab')2 Fr. These data have implications for designing therapeutic approaches directed toward TCR targeting in humans.
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Gerbitz, Armin, Madhusudhanan Sukumar, Florian Helm, Andrea Wilke, Thomas Kammertoens, Christian Friese, Josef Mautner, and Georg Bornkamm. "Mechanisms of Antigen Dependent and Independent Rejection of High Grade B-Cell Lymphoma in a Murine Model." Blood 114, no. 22 (November 20, 2009): 4091. http://dx.doi.org/10.1182/blood.v114.22.4091.4091.
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Abstract Abstract 4091 Poster Board III-1026 The rejection of Non Hodgkin Lymphomas expressing foreign, for example viral, antigens is compromised despite the presence of specific T-cells. The underlying immunosuppressive mechanisms are poorly understood. Using a transgenic mouse lymphoma model, where the proto-oncogene c-myc is driven by parts of the immunoglobulin lambda locus representing a t(8;22) translocation as found in Burkitt's lymphoma, we investigated the anti-lymphoma activity of specific T-cells. By retroviral transduction of a specific foreign antigen (chicken Ovalbumin-IRES-GFP, OVA) into cell lines from primary c-myc transgenic lymphomas we established a syngeneic model that would allow us to address the role of interferon gamma signalling in rejection of high grade lymphomas. All primary lymphoma cells displayed normal MHC class I and II levels on the surface when compared to wildtype splenic B-cells. This expression could be enhanced by treatment with interferon gamma (IFNg,100U/ml) up to 10 fold. When retrovirally OVA-transduced lymphoma cells were injected into either wildtype or GFP transgenic recipients, animals displayed a significant delay in lymphoma growth compared to non transduced or IRES-GFP transduced control cell lines. 80% of the recipient mice rejected OVA expressing lymphomas. By contrast, we observed 100% mortality when GFP expressing control lymphomas were injected in GFP transgenic recipients, which are tolerant for GFP. Developing OVA expressing lymphomas (20%) displayed a loss of GFP expression indicating a selection for antigen negative cells (p=0.001). In spleens from mice rejecting OVA-expressing lymphomas we found up to 1.8% SIINFEKL specific T-cells. To gain more mechanistic insights, we transferred OVA expressing lymphoma cells into IFNg, Stat1-/- or IFNg-/-receptor deficient recipients. Lack of STAT1-/- or IFNg-receptor on the recipient side or inability to secrete IFNg was associated with fast lymphoma progression and growth was not different when compared to non transduced, antigen negative cell lines. When IFNg-receptor or STAT1 deficient OVA expressing cell lines were transferred into wildytpe mice, rejection was not influenced. Outgrowing OVA expressing lymphomas in wildtype mice displayed a high MHC class I and II expression compared to the cell line prior to injection. MHC induction was absent in lymphomas transferred to Stat1 or IFNg deficient recipients. Depletion of NK cells by anti AsialoGM antibody in wildtype recipients resulted in a significant reduction of disease free survival (80% vs. 50%, p=0.002) and animals developed larger tumors which were eventually rejected resulting in a comparable overall survival. In peripheral blood of NK depleted mice significantly more OVA specific T-cells were detectable through pentamer staining. When lymphoma cell lines were injected into Rag1-/- mice, NK cell mediated rejection was also significantly impaired upon depletion. Our results suggest that T-cell mediated rejection of high grade B-cell lymphomas is strongly dependent on host IFNg secretion and that NK cells substantially contribute to T-cell mediated rejection. Disclosures: No relevant conflicts of interest to declare.
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Jacobsen, Elizabeth A., Sergei I. Ochkur, Ralph S. Pero, Anna G. Taranova, Cheryl A. Protheroe, Dana C. Colbert, Nancy A. Lee, and James J. Lee. "Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells." Journal of Experimental Medicine 205, no. 3 (March 3, 2008): 699–710. http://dx.doi.org/10.1084/jem.20071840.
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The current paradigm surrounding allergen-mediated T helper type 2 (Th2) immune responses in the lung suggests an almost hegemonic role for T cells. Our studies propose an alternative hypothesis implicating eosinophils in the regulation of pulmonary T cell responses. In particular, ovalbumin (OVA)-sensitized/challenged mice devoid of eosinophils (the transgenic line PHIL) have reduced airway levels of Th2 cytokines relative to the OVA-treated wild type that correlated with a reduced ability to recruit effector T cells to the lung. Adoptive transfer of Th2-polarized OVA-specific transgenic T cells (OT-II) alone into OVA-challenged PHIL recipient mice failed to restore Th2 cytokines, airway histopathologies, and, most importantly, the recruitment of pulmonary effector T cells. In contrast, the combined transfer of OT-II cells and eosinophils into PHIL mice resulted in the accumulation of effector T cells and a concomitant increase in both airway Th2 immune responses and histopathologies. Moreover, we show that eosinophils elicit the expression of the Th2 chemokines thymus- and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in the lung after allergen challenge, and blockade of these chemokines inhibited the recruitment of effector T cells. In summary, the data suggest that pulmonary eosinophils are required for the localized recruitment of effector T cells.
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Kurts, C., W. R. Heath, F. R. Carbone, J. Allison, J. F. Miller, and H. Kosaka. "Constitutive class I-restricted exogenous presentation of self antigens in vivo." Journal of Experimental Medicine 184, no. 3 (September 1, 1996): 923–30. http://dx.doi.org/10.1084/jem.184.3.923.
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Ovalbumin (OVA)-specific CD8+ T cells from the T cell receptor-transgenic line OT-I (OT-I cells) were injected into unirradiated transgenic RIP-mOVA mice, which express a membrane-bound form of OVA (mOVA) in the pancreatic islet beta cells and the renal proximal tubular cells. OT-I cells accumulated in the draining lymph nodes (LN) of the kidneys and pancreas and in no other LN. They displayed an activated phenotype and a proportion entered cell cycle. Unilateral nephrectomy 7-13 d before inoculation of OT-I cells into RIP-mOVA mice allowed the injected T cells to home only to the regional LN of the remaining kidney (and pancreas), but when the operation was performed 4 h before injecting the T cells, homing to the LN of the excised kidney was evident. When the bone marrow of RIP-mOVA mice was replaced with one of a major histocompatibility haplotype incapable of presenting OVA to OT-I cells, no homing or activation was detectable. Therefore, OT-I cells were activated by OVA presented by short-lived antigen-presenting cells of bone marrow origin present in the draining LN of OVA-expressing tissue. These results provide the first evidence that tissue-associated "self" antigens can be presented in the context of class I via an exogenous processing pathway. This offers a constitutive mechanism whereby T cells can be primed to antigens that are present in nonlymphoid tissues, which are not normally surveyed by recirculating naive T cells.
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Baird, A. M., and D. C. Parker. "Analysis of low zone tolerance induction in normal and B cell-deficient mice." Journal of Immunology 157, no. 5 (September 1, 1996): 1833–39. http://dx.doi.org/10.4049/jimmunol.157.5.1833.
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Abstract To investigate the role of B cells as APCs in acquired tolerance induced by low dose soluble protein Ags, normal and B cell-deficient adult mice were injected i.v. with repeated low doses (10 microgram) of deaggregated OVA, then challenged with OVA in CFA. In animals treated with deaggregated OVA, the in vitro proliferative responses of lymph node T cells to OVA were significantly reduced, and production of the Th1 cytokine, IFN-gamma, in response to OVA was reduced to undetectable levels. This occurred in both normal and B cell-deficient treated animals. B cells were also unnecessary for self tolerance of T cells to the transgenic self Ag, hen egg lysozyme, in a strain with a very low serum lysozyme concentration. Partial low zone tolerance induced by deaggregated, low dose OVA was selective for T cell responses as measured by in vitro proliferation and IL-2 and IFN-gamma production, because Ab responses of B cell-sufficient mice to this T cell-dependent Ag were largely unaffected. Both treated and untreated animals produced equivalent titers of anti-OVA Abs, predominantly of the IgG1 and IgG2b isotypes, following challenge with OVA in CFA.
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Lee, W. T., J. Cole-Calkins, and N. E. Street. "Memory T cell development in the absence of specific antigen priming." Journal of Immunology 157, no. 12 (December 15, 1996): 5300–5307. http://dx.doi.org/10.4049/jimmunol.157.12.5300.
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Abstract Numerous studies have shown that memory T cell development is Ag dependent and specific. In the present study, we show that memory responses can be made against an Ag to which there has been no prior exposure. In unimmunized DO11.10 mice, which carry alpha and beta transgenes that encode a TCR specific for OVA, CD45RB(low) memory cells express the transgenic TCR. These cells can be stimulated by OVA to proliferate and perform typical memory functions, such as secrete diverse lymphokines and provide cognate help to B cells, despite the fact that the mice were never exposed to OVA. Thus, memory cells can be generated in the absence of specific Ag. The data also demonstrate that the transgenic TCR-bearing memory T cells possess endogenous TCR alpha-chains, which permit the expression of a second TCR. In DO11.10/RAG(-/-) mice, the endogenous alpha-chains are eliminated, and the T cells can only express the transgenic TCR. In these mice, no memory cells were observed. Thus, it is the additional TCR that appears to drive memory cell generation. Once induced, memory function may be triggered through the transgenic receptor. Since dual TCR-bearing cells have been shown to exist in nontransgenic mice and humans, our results provide evidence that one mechanism for the maintenance of memory responses to a specific Ag is through stimulation of the second TCR by another Ag. Further, these findings have important implications for understanding aberrant immune responses, such as those that occur in autoimmunity.
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Carl, Joseph W., Pramod Joshi, Caroline C. Whitacre, Yang Liu, and Xue-Feng Bai. "CD24 inhibits thymic deletion of myelin antigen-specific T cells (129.34)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S224. http://dx.doi.org/10.4049/jimmunol.178.supp.129.34.
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Abstract CD24 is a glycosylphosphatidylinositol (GPI) anchored cell surface glycoprotein that is expressed in hematopoietic cells and cells of the central nervous system (CNS). We have previously shown that CD24 is required for the induction of experimental autoimmune encephalomyelitis (EAE), an experimental model of human disease multiple sclerosis. In CD24−/− mice, normal levels of myelin oligodendrocyte glycoprotein (MOG) specific T cell were primed, however these T cells were non-pathogenic. To understand this issue, we bred CD24−/− mice with 2D2 TCR transgenic mice, which bear TCR specific to MOG, and generated 2D2 TCR transgenic mice with or without CD24. Here we show that 2D2 TCR transgenic mice with CD24-deficiency (2D2/CD24−/−) have remarkably withered thymus. In peripheral lymphoid organs, transgenic T cells from 2D2/CD24−/− mice have an immature phenotype (CD4−CD8−), do not respond to MOG peptide stimulation, and fail to cause autoimmune inflammation in the CNS and optical nerves. In contrast, OT-2 TCR transgenic mice with CD24 deficiency (OT-2/CD24−/−), which bear TCR specific to chicken ovalbumin (OVA), have normal thymus and their peripheral T cells have a normal response to OVA peptide. These data suggest that CD24 inhibits thymic deletion of myelin antigen, but not foreign antigen-reactive T cells.
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Mullen, Craig A., Ulker Kocak, Joanne L. Shaw, and Shahram Mori. "Augmentation of Post-Transplant Immunity: Antigen Encounter at Time of Hematopoietic Stem Cell Transplantation Enhances Antigen-Specific Donor T Cell Responses in the Post-Transplant Repertoire." Blood 104, no. 11 (November 16, 2004): 2246. http://dx.doi.org/10.1182/blood.v104.11.2246.2246.
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Abstract After transplant the immune system is reconstituted by cells derived from both hematopoietic stem cells and peripheral expansion of differentiated donor T cells. Immune function is poor despite transplantation of mature lymphocytes from immune competent donors. We tested the hypothesis that early antigen encounter at the time of cell transplant would enhance desired donor T cell responses in the post-transplant repertoire. 2 independent models of peptide-specific T cell responses were studied. Model 1 : The model for CD4 cells employed T cells from transgenic DO11.11 mice that constitutively express the T cell receptor for the class II restricted ovalbumin (OVA) peptide 323–339. Fig 1: Early exposure to OVA antigen enhances clonal expansion of OVA specific transgenic T-cells following syngeneic BMT. Lethally irradiated BALB/c mice were injected with 300 μg of OVA peptide in CFA or CFA alone subcutaneously one day before transplantation (D-1). The transplanted mice received 2x106 transgenic OVA specific T-cells and 6x106 non-transgenic naive BALB/c bone marrow cells. At 2 days (A) and 7weeks (B) following BMT, draining lymph nodes were isolated and examined for the presence of OVA-specific T-cells using FITC-labeled KJ-126 antibody and PE-labeled anti mouse CD4 antibody. Naïve BALB/c animals were used as negative controls (C). The absolute number of antigen-specific T-cells was determined by multiplying the total cells recovered with the percentage of OVA-specific CD4+ T-cells identified by flow. Figure Figure Model 2: The model for CD8 cells employed nontransgenic H2-Db-restricted T cell responses to the influenza nucleoprotein peptide 366–374. Fig 2: Antigen specific CD8+ cells in antigen-exposed animals are functionally active. Donor SW mice were immunized three times by ip injection of virus-infected spleen cells. Recipient C57BL/6 animals underwent BMT using influenza-immune donors spleen cells and bone marrow (10x106 and 4x106 respectively). Some transplant recipients were exposed to influenza virus on D-1. Ten days following BMT, the animals were sacrificed and spleens were isolated and stimulated in vitro with 2 μg of NP peptide. After two rounds of stimulation, the splenocytes were assayed by intracellular cytokine assay for the secretion of IFNg by staining with PE-anti IFNγ and FITC-anti-CD8 antibodies. The results are representative of three experiments (total number n=4/experimental group). Figure Figure Encounter with specific antigen at the time of T cell transplantation led to clonal expansion of donor T cells and preservation of donor T cell function in the post-transplant immune environment. Antigen-specific donor T cell function was poor if antigen encounter was delayed or omitted. Severe parent>F1 graft versus host reactions blocked the effect of early antigen exposure.
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Chou, Cassie K., Ryan M. Teague, Xiaoxia Tan, Timothy L. Ratliff, Norman M. Greenberg, and Philip D. Greenberg. "Characterization of T cell responses specific for a self-antigen expressed in the mouse prostate (40.23)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 40.23. http://dx.doi.org/10.4049/jimmunol.182.supp.40.23.
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Abstract OBJECTIVE: Examine if functional prostate-specific T cells exist in mice and determine if such T cells might be harnessed for prostate cancer therapy. METHODS: Studies were performed in transgenic mice (POET) expressing ovalbumin (OVA) under control of a prostate-specific promoter and double transgenic POETxOTI and POETxOTII mice, which contain OVA-specific CD8 or CD4 T cells, respectively. RESULTS: Double transgenic mice revealed incomplete central deletion of OTI and OTII cells, with functional prostate-specific T cells still present in the periphery. To model the fate of prostate-specific T cells in which the self-protein is not expressed during development, we transferred OTI or OTII cells into POET mice. While most transferred OTI cells were deleted, the persisting OTI cells were antigen experienced and capable of expanding and inducing prostate inflammation. Transferred OTII cells by contrast maintained a naïve and responsive phenotype. CONCLUSIONS: Antigen experienced prostate-specific CD8 T cells persist, can be induced to expand and infiltrate the normal prostate, and thus may prove useful for cancer therapy. CD4 T cells specific for the same prostate antigen remain naïve, suggesting limited presentation by APC. We are generating TRAMPxPOET mice, which develop OVA-expressing prostate cancer, to study targeting self-antigens for tumor therapy. Supported by the NCI & a CRI Predoctoral Fellowship
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Tedla, Mebrahtu G., Alison L. Every, and Jean-Pierre Y. Scheerlinck. "Measuring the Manipulation of T Helper Immune Responses by Schistosoma mansoni." International Journal of Molecular Sciences 23, no. 3 (January 27, 2022): 1462. http://dx.doi.org/10.3390/ijms23031462.
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Schistosoma mansoni uses different mechanisms to escape its host’s immunity. Understanding the ability of memory T cells to withstand this pathogen’s manipulation is important for the development of effective vaccines against this immunomodulatory pathogen. In this study, ovalbumin (OVA) transgenic S. mansoni is used as a tool to investigate whether fully differentiated Th1, Th2 and Th17 cells are able to withstand pathogen manipulation. Naïve T cells from OT-II T cell receptor transgenic mice with a specificity for OVA were differentiated into Th1, Th2, and Th17 polarised memory cells in vitro. These cells were adoptively transferred into recipient mice to investigate whether these polarised immune memory T cells are resilient in the face of pathogen-mediated manipulation. After transferring memory cells, mice were challenged with OVA-transduced S. mansoni eggs as well as wild-type controls. The in vitro differentiated Th1, Th2 and Th17 memory cells continued to produce the same cytokines when challenged by OVA-expressing S. mansoni eggs as to these they produced when transferred in vivo, suggesting that the Th phenotypes of the memory T cells remains unaltered in the face of stimulation by S. mansoni. The ability of memory T cells to remain resilient to manipulation by the parasite suggests that vaccines might be able to produce immune memory responses able to withstand S. mansoni immune manipulation and hence protect the host from infection.
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Van Houten, N., and S. F. Blake. "Direct measurement of anergy of antigen-specific T cells following oral tolerance induction." Journal of Immunology 157, no. 4 (August 15, 1996): 1337–41. http://dx.doi.org/10.4049/jimmunol.157.4.1337.
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Abstract T cell tolerance induced by oral administration of Ag may be the result of either deletion or functional inactivation of Ag-specific T cells. OVA p(323-339)-specific TCR transgenic (Tg+) lymphocytes were transplanted into BALB/c recipients. Chimeric mice were fed OVA and subsequently challenged with the peptide in CFA. Tolerance was then assessed by measurement of lymph node (LN) cell proliferation in response to the peptide, and deletion was assessed by measuring the frequency Tg+ T cells by flow cytometry. Lymphocytes from chimeric mice fed OVA showed a dose-dependent decline in their proliferative response to the peptide in vitro, compared with immunized control mice that were not fed OVA. Calculation of proliferative potential per Tg+ cell demonstrates that nonresponsiveness due to feeding Ag results in the induction of anergy in the LN. In addition, analysis of intestinal intraepithelial lymphocytes following feeding of OVA did not show evidence of trafficking of LN T cells to the small intestine intraepithelial nor lamina propria compartments.
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Alcorn, John F., Karina Ckless, Amy L. Brown, Amy S. Guala, Jay K. Kolls, Matthew E. Poynter, Charles G. Irvin, Albert van der Vliet, and Yvonne M. W. Janssen-Heininger. "Strain-dependent activation of NF-κB in the airway epithelium and its role in allergic airway inflammation." American Journal of Physiology-Lung Cellular and Molecular Physiology 298, no. 1 (January 2010): L57—L66. http://dx.doi.org/10.1152/ajplung.00037.2009.
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NF-κB activation in the airway epithelium has been established as a critical pathway in ovalbumin (Ova)-induced airway inflammation in BALB/c mice (Poynter ME, Cloots R, van Woerkom T, Butnor KJ, Vacek P, Taatjes DJ, Irvin CG, Janssen-Heininger YM. J Immunol 173: 7003–7009, 2004). BALB/c mice are susceptible to the development of allergic airway disease, whereas other strains of mice, such as C57BL/6, are considered more resistant. The goal of the present study was to determine the proximal signals required for NF-κB activation in the airway epithelium in allergic airway disease and to unravel whether these signals are strain-dependent. Our previous studies, conducted in the BALB/c mouse background, demonstrated that transgenic mice expressing a dominant-negative version of IκBα in the airway epithelium (CC10-IκBαSR) were protected from Ova-induced inflammation. In contrast to these earlier observations, we demonstrate here that CC10-IκBαSR transgenic mice on the C57BL/6 background were not protected from Ova-induced allergic airway inflammation. Consistent with this finding, Ova-induced nuclear localization of the RelA subunit of NF-κB was not observed in C57BL/6 mice, in contrast to the marked nuclear presence of RelA in BALB/c mice. Evaluation of cytokine profiles in bronchoalveolar lavage demonstrated elevated expression of TNF-α in BALB/c mice compared with C57BL/6 mice after an acute challenge with Ova. Finally, neutralization of TNF-α by a blocking antibody prevented nuclear localization of RelA in BALB/c mice after Ova challenge. These data suggest that the mechanism of response of the airway epithelium of immunized C57BL/6 mice to antigen challenge is fundamentally different from that of immunized BALB/c mice and highlight the potential importance of TNF-α in regulating epithelial NF-κB activation in allergic airway disease.
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Qazi, Khaleda Rahman, Ulf Gehrmann, Emilie Domange Jordö, Mikael C. I. Karlsson, and Susanne Gabrielsson. "Antigen-loaded exosomes alone induce Th1-type memory through a B cell–dependent mechanism." Blood 113, no. 12 (March 19, 2009): 2673–83. http://dx.doi.org/10.1182/blood-2008-04-153536.
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Abstract Exosomes are nanovesicles harboring proteins important for antigen presentation. We compared the potency of differently loaded exosomes, directly loaded with OVA323-339 peptide (Pep-Exo) or exosomes from OVA-pulsed DCs (OVA-Exo), for their ability to induce specific T-cell proliferation in vitro and in vivo. Both Pep-Exo and OVA-Exo elicited specific transgenic T-cell proliferation in vitro, with the Pep-Exo being more efficient. In contrast, only OVA-Exo induced specific T-cell responses in vivo highlighting the importance of indirect loading strategies in clinical applications. Coadministration of whole OVA overcame the unresponsiveness with Pep-Exo but still elicited a lower response compared with OVA-Exo. In parallel, we found that OVA-Exo not only augmented the specific T-cell response but also gave a Th1-type shift and an antibody response even in the absence of whole OVA. We detected IgG2a and interferon-γ production from splenocytes showing the capability of exosomes to provide antigen for B-cell activation. Furthermore, we found that B cells are needed for exosomal T-cell stimulation because Bruton tyrosine kinase–deficient mice showed abrogated B- and T-cell responses after OVA-Exo immunization. These findings reveal that exosomes are potent immune regulators and are relevant for the design of vaccine adjuvants and therapeutic intervention strategies to modulate immune responses.
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Porrett, Paige, Brendan Barton, Rebecca Klahr, and John Wherry. "Pregnancy primes anti-fetal T cell memory capable of allograft destruction (TRAN3P.874)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 202.13. http://dx.doi.org/10.4049/jimmunol.192.supp.202.13.
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Abstract Pregnancy-induced anti-fetal antibody can destroy allografts and excludes many women from transplantation, but anti-fetal T cell responses are poorly understood and are not currently evaluated in potential organ recipients. To test whether pregnancy (PG) primes graft-reactive T cell memory, we compared Ova skin graft survival (GS) between naive B6 mice (N), mice mated to Ova transgenic (tg) males (Ova PG-sensitized; OP), or mice sensitized by a previous Ova skin graft (OS). Skin grafts were placed 30 days after either Ova pup delivery (OP group) or after rejection of an Ova skin graft (OS group). OP females rapidly rejected Ova skin grafts with second set kinetics identical to OS females [GS (days): 11.3±1.5(OP) vs. 10.3±0.6(OS) vs. 15±0.7(N); p<.01]. To test the effects on antigen-specific T cells, mice were injected with Ova-specific TCR tg T cells. Flow cytometric analysis 30 days after pup delivery revealed memory T cell differentiation in response to fetal antigen [%anti-Ova CD8+CD44+CD62L-: 85%(Ova-mated) vs. 38%(Balb/c-mated)]. OP mice also produced enhanced effector T cells upon secondary challenge with an Ova skin graft [%anti-Ova CD8+IFNγ+: 60%(OP) vs. 43%(Balb-mated) vs. 35%(N)]. These results indicate that PG can prime T cell memory that gives rise to secondary effector T cells that mediate rapid graft destruction. Stimulation of PG-induced anti-fetal T cell memory may contribute to the inferior GS observed in women who receive a transplant from a child or spouse.
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Steinaa, L., P. B. Rasmussen, A. Gautam, and S. Mouritsen. "Breaking B-cell Tolerance and CTL Tolerance in three OVA-transgenic Mouse Strains Expressing Different Levels of OVA." Scandinavian Journal of Immunology 67, no. 2 (February 2008): 113–20. http://dx.doi.org/10.1111/j.1365-3083.2007.02045.x.
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Lin, Jing-Wen, Tovah N. Shaw, Takeshi Annoura, Aurélie Fougère, Pascale Bouchier, Séverine Chevalley-Maurel, Hans Kroeze, et al. "The Subcellular Location of Ovalbumin in Plasmodium berghei Blood Stages Influences the Magnitude of T-Cell Responses." Infection and Immunity 82, no. 11 (August 25, 2014): 4654–65. http://dx.doi.org/10.1128/iai.01940-14.
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ABSTRACTModel antigens are frequently introduced into pathogens to study determinants that influence T-cell responses to infections. To address whether an antigen's subcellular location influences the nature and magnitude of antigen-specific T-cell responses, we generatedPlasmodium bergheiparasites expressing the model antigen ovalbumin (OVA) either in the parasite cytoplasm or on the parasitophorous vacuole membrane (PVM). For cytosolic expression, OVA alone or conjugated to mCherry was expressed from a strong constitutive promoter (OVAhsp70orOVA::mCherryhsp70); for PVM expression, OVA was fused to HEP17/EXP1 (OVA::Hep17hep17). Unexpectedly, OVA expression inOVAhsp70parasites was very low, but when OVA was fused to mCherry (OVA::mCherryhsp70), it was highly expressed. OVA expression inOVA::Hep17hep17parasites was strong but significantly less than that inOVA::mCherryhsp70parasites. These transgenic parasites were used to examine the effects of antigen subcellular location and expression level on the development of T-cell responses during blood-stage infections. While all OVA-expressing parasites induced activation and proliferation of OVA-specific CD8+T cells (OT-I) and CD4+T cells (OT-II), the level of activation varied:OVA::Hep17hep17parasites induced significantly stronger splenic and intracerebral OT-I and OT-II responses than those ofOVA::mCherryhsp70parasites, butOVA::mCherryhsp70parasites promoted stronger OT-I and OT-II responses than those ofOVAhsp70parasites. Despite lower OVA expression levels,OVA::Hep17hep17parasites induced stronger T-cell responses than those ofOVA::mCherryhsp70parasites. These results indicate that unconjugated cytosolic OVA is not stably expressed inPlasmodiumparasites and, importantly, that its cellular location and expression level influence both the induction and magnitude of parasite-specific T-cell responses. These parasites represent useful tools for studying the development and function of antigen-specific T-cell responses during malaria infection.
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Ding, Chuanlin, Li Wang, Hayma Al-Gwahi, Jose Marroquin, Richard Hansen, and jun yan. "T and B Cell Immune Responses to Tumor Antigen MUC1 are Induced by Targeting Antigen to B Lymphocytes (50.20)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S94. http://dx.doi.org/10.4049/jimmunol.178.supp.50.20.
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Abstract To test the hypothesis that MUC1 specific T cell responses may be induced by targeting MUC1 to B cells in the presence of CpG ODN adjuvant, we first conjugated a model Ag ovalbumin (OVA) with anti-CD19 mAb as a means to target Ag to B cells. OVA TCR transgenic CD8 T cells (OT-I) and CD4 T cells (OT-II) were used to exam if targeting OVA to B cells through CD19 leads to Ag presentation in the context of MHC class I and II for T cell activation. The results indicated that OVA conjugates could significantly induce CD4 and CD8 T cells proliferation and activation. These expanded T cells were not deleted or anergized, and were characterized by proliferation (OT-II T cells) and IFN-γ release (OT-I T cells) in response to OVA peptide. CpG ODN could significant enhance the survival of CD8+ T cells and IFN-γ production. To further extend these observations to tumor Ag, MUC1 transgenic (Tg) mice that are tolerized to MUC1 Ag, resembling cancer patients, were immunized with anti-CD19 conjugated MUC1 with or without CpG ODN. The data demonstrated that MUC1 conjugates in combination with CpG ODN elicit high-titer anti-MUC1 Abs. In addition, MUC1-specific cytotoxicity and vigorous IFN-γ secretion was generated. In contrast, Tg mice immunized with MUC1 peptide, even in the presence of CpG ODN, did not elicit Ab production and T cell responses. These results indicated that Ag targeted to B cells via CD19 in combination with TLR agonist could reverse immunological tolerance to MUC1 Ag and generate MUC1-specific B cell and T cell responses.
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Mishra, Pankaj, Christina Rozo, Benevenia Joseph, and William Gause. "Titanium used in the prosthetic devices may act as an adjuvant driving Th2 cell differentiation (44.15)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 44.15. http://dx.doi.org/10.4049/jimmunol.184.supp.44.15.
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Abstract Inflammation contributing to periprosthetic osteolysis following joint replacement is a potential complication of arthroplastic surgery. The components of the prosthetic device that elicit inflammation and the characteristics of the innate and adaptive immune response that contribute to inflammation are as yet little studied. The prosthetic material Titanium (Ti) was examined for adjuvant properties. Mice were immunized with the Ti particle (12.5 mg) + LPS-free OVA protein (50 µg) and found to elicit elevated levels of serum IgE, IgG1 and IgG2a compared to OVA alone. CFSE labeled transgenic OVA-specific DO11.10 CD4+ cells were transferred to recipient BALB/c mice and inoculated i.p two days later with Ti plus OVA323-339 peptide or with OVA323-339 peptide alone. Five days after inoculation, CFSE fluorescence analysis showed that donor CD4+, KJ1.26+ DO11.10 T cells had undergone markedly more cell cycling in recipient mice receiving Ti+OVA compared to recipient mice administered OVA alone. OVA-specific ELISPOT assays of cell suspensions from draining lymph nodes showed marked increases in DO11.10 T cell IL-4 and lesser elevations in IFN-γ expression from mice inoculated with Ti + OVA compared to mice immunized with OVA peptide alone. These studies suggest that Ti can act as an adjuvant in vivo to induce naïve T cell differentiation to cytokine producing effector T cells indicating that this inert nanoparticle has potent inflammatory characteristics.
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Ebeling, Cory, Ramses Ilarraza, and Darryl Adamko. "Novel method for the development of regulatory T cells (166.22)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 166.22. http://dx.doi.org/10.4049/jimmunol.186.supp.166.22.
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Abstract Background: Regulatory T cells (Treg) are important in the inhibition of inflammatory disorders, like asthma. Unfortunately, current protocols used to develop them in vitro for study rely on complicated cloning methods that may not represent biologically relevant Treg. LPS-free ovalbumin (OVA) given intranasal (i.n.) can induce mucosal tolerance in mice. Therefore, we hypothesized that Dendritic cells (DCs) taken from the draining lymph nodes (LNs) of mice given LPS-free OVA would induce Treg in vitro. Methods: Mice were given i.n. LPS-free OVA. 24 h later cervical and bronchial LNs were excised and DCs were isolated (~98% purity). DCs were cultured in vitro with transgenic OVA-specific T cells for four days. The development of Treg was assessed by flowcytometry (Foxp3 expression), ELISA (IL-10 production), and inhibition of T cell proliferation (CFSE staining/BrdU uptake). Finally, we studied the effectiveness of these cells to inhibit the development of AHR in a mouse model of asthma. Results: T cells from mice treated with LPS-free OVA showed high levels of Foxp3 expression, high IL-10 production, and the ability to inhibit OVA specific T cells in vitro. compared to control mice. Furthermore, T cells from LPS-free OVA treated mice prevented the development of AHR when given to mice before OVA challenge (i.n.). Conclusion: We believe our protocol could represent an alternative method to develop Treg cells for study.
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Sun, Jiaren, Bernadette Dirden-Kramer, Komei Ito, Peter B. Ernst, and Nancy Van Houten. "Antigen-Specific T Cell Activation and Proliferation During Oral Tolerance Induction." Journal of Immunology 162, no. 10 (May 15, 1999): 5868–75. http://dx.doi.org/10.4049/jimmunol.162.10.5868.
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Abstract One of several routes of achieving immunologic tolerance is through functional inactivation of Ag-specific T cells. Oral administration of Ag can allow survival of the Ag-specific T cells that are functionally anergic. The aim of this study was to investigate whether functional inactivation of Ag-specific T cells is directed through an activation process and to further define the differentiative pathways and functional characteristics of anergic T cells. Mice were transplanted with OVA-specific TCR-transgenic T cells and either fed OVA or immunized s.c. with the OVA peptide 323–339 in CFA. OVA-specific T cells from OVA-fed mice were unresponsive to restimulation in vitro within 48–72 h after treatment. In vivo, however, T cell proliferation was detected by 5,6-carboxy-succinimidyl-fluoresceine-ester intensity changes in OVA-specific T cells. The mesenteric lymph nodes (LNs) from OVA-fed mice more frequently contained OVA-specific dividing cells in vivo than those in the peripheral LNs, and the reciprocal was observed following s.c. immunization of the OVA peptide in CFA. The induction of anergy in OVA-fed mice was accompanied by rapid up-regulation of CD69 and CTLA-4, later down-regulation of CD45RB on OVA-specific T cells, and a marked decrease in T cell secretion of IL-2, IL-10, and IFN-γ after OVA restimulation in vitro. Results from this study indicate that the inductive phase of oral tolerance is preceded by Ag-specific T cell activation in vivo, proliferation in the regional draining LNs, and differentiation into a memory-like state. These results indicate that Ag-directed differentiation occurs as a part of T cell tolerance through anergy.
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Brimnes, Marie K., Laura Bonifaz, Ralph M. Steinman, and Thomas M. Moran. "Influenza Virus–induced Dendritic Cell Maturation Is Associated with the Induction of Strong T Cell Immunity to a Coadministered, Normally Nonimmunogenic Protein." Journal of Experimental Medicine 198, no. 1 (July 7, 2003): 133–44. http://dx.doi.org/10.1084/jem.20030266.
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We evaluated the proposal that during microbial infection, dendritic cells (DCs) undergo maturation and present a mixture of peptides derived from the microbe as well as harmless environmental antigens. Mice were exposed to an aerosol of endotoxin free ovalbumin (OVA) in the absence or presence of influenza virus. In its absence, OVA failed to induce B and T cell responses and even tolerized, but with influenza, OVA-specific antibodies and CD8+ cytolytic T lymphocytes developed. With or without infection, OVA was presented selectively in the draining mediastinal lymph nodes, as assessed by the comparable proliferation of infused, CD8+ and CD4+, TCR transgenic T cells. In the absence of influenza, these OVA-specific T cells produced little IL-2, IL-4, IL-10, and IFN-γ, but with infection, both CD4+ and CD8+ T cells made high levels of IL-2 and IFN-γ. The OVA plus influenza-treated mice also showed accelerated recovery to a challenge with recombinant vaccinia OVA virus. CD11c+ DCs from the mediastinal lymph nodes of infected mice selectively stimulated both OVA- and influenza-specific T cells and underwent maturation, with higher levels of MHC class II, CD80, and CD86 molecules. The relatively slow (2–3 d) kinetics of maturation correlated closely to the time at which OVA inhalation elicited specific antibodies. Therefore respiratory infection can induce DC maturation and simultaneously B and T cell immunity to an innocuous antigen inhaled concurrently.
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Perchellet, Antoine, and Margaret Petroff. "Antigen-specific tolerance to the fetus in murine pregnancy (89.9)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 89.9. http://dx.doi.org/10.4049/jimmunol.182.supp.89.9.
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Abstract Tolerance of the maternal immune system is believed to be important for successful pregnancy as the fetus is semi-allogeneic. We examined maternal T cell tolerance in mice using a system in which a model antigen, ovalbumin (OVA), is expressed exclusively in the fetus. This is achieved by breeding females that lack OVA to male mice that transgenically express membrane-bound OVA under the control of the β-actin promoter. By employing T cell receptor (TCR) transgenic mice specific for a MHC class II-restricted epitope of OVA (OT-II) as mothers, we investigated the fate of fetus-specific CD4+ T cells during gestation. OVA-specific CD4+ T cells displayed an activated phenotype in the spleen and lymph nodes of OVA-bred OT-II mice, consistent with their encounter of fetal antigen in peripheral lymphoid tissues. A small percentage of OVA-specific CD4+ T cells were deleted in the periphery of OVA-bred OT-II mice, with evidence of TCR downregulation in a portion of the remaining T cells. Interestingly, deletion and TCR downregulation were also observed in the thymus of OVA-bred OT-II mice, suggesting that fetal antigen may affect central tolerance. These preliminary data indicate that fetal antigen-specific maternal CD4+ T cells are tolerized during gestation. This project is supported by NIH grants HD045611 and HD049480, and a Lied Endowed Basic Science Pilot grant. A. Perchellet is supported by NIH training grant T32HD007455.
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Eggena, Mark P., Lucy S. K. Walker, Vijaya Nagabhushanam, Luke Barron, Anna Chodos, and Abul K. Abbas. "Cooperative Roles of CTLA-4 and Regulatory T Cells in Tolerance to an Islet Cell Antigen." Journal of Experimental Medicine 199, no. 12 (June 21, 2004): 1725–30. http://dx.doi.org/10.1084/jem.20040124.
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Adoptive transfer of ovalbumin (OVA)-specific T cells from the DO.11 TCR transgenic mouse on a Rag−/− background into mice expressing OVA in pancreatic islet cells induces acute insulitis and diabetes only if endogenous lymphocytes, including regulatory T cells, are removed. When wild-type OVA-specific/Rag−/− T cells, which are all CD25−, are transferred into islet antigen–expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4−/−/Rag−/− OVA-specific T cells (also CD25−) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. Further, CTLA-4 and regulatory T cells act cooperatively to maintain tolerance, indicating that the function of CTLA-4 is independent of regulatory cells, and deficiency of both is required to induce pathologic immune responses against the islet self-antigen.
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Dobrzynski, Eric, Federico Mingozzi, Yi-Lin Liu, Elisabeth Bendo, Ou Cao, Lixin Wang, and Roland W. Herzog. "Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer." Blood 104, no. 4 (August 15, 2004): 969–77. http://dx.doi.org/10.1182/blood-2004-03-0847.
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AbstractImmune responses to the therapeutic gene product are a potentially serious complication in treatment of genetic disease by gene therapy. Induction and maintenance of immunologic hypo-responsiveness to the therapeutic antigen is therefore critical to the success of gene-based treatment of inherited protein deficiency. Here, we demonstrate induction of antigen-specific CD4+ T-cell tolerance to a secreted transgene product (ovalbumin, ova) in ova-specific T-cell receptor (TCR) transgenic mice by hepatic adeno-associated virus (AAV)–mediated gene transfer. Transduced mice maintained stable circulating ova levels without evidence of an immune response. Lymph node cells and splenocytes were hypo-responsive to ova as early as day 10 after gene transfer. Numbers of TCR+CD4+ cells were reduced in secondary lymphoid organs and in the thymus by 1 to 2 months after vector administration. The remaining TCR+CD4+ cell population was anergic to ova antigen in vitro and enriched for CD25+ cells. These data provide direct evidence that transgene expression following in vivo viral gene transfer can induce CD4+ T-cell tolerance to the transgene product, involving anergy and deletion mechanisms.
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Zhai, Yougang, Lan Zhou, Zhenyu Zhong, and Liang Qiao. "Resting B cells as Inducers of Antigen-Specific T Regulatory Cells (83.22)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 83.22. http://dx.doi.org/10.4049/jimmunol.184.supp.83.22.
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Abstract We have previously shown that resting B cells are able to expand T regulatory cells through TGF-beta3 whereas activated B cells induce increased apoptosis of T regulatory cells. Thus, we hypothesize that resting B cells can be used to induce antigen-specific T regulatory cells. To test our hypothesis, we isolate resting B cells from mice and load the cells with Ova, and then adoptively transfer the B cells to Ova-specific TCR transgenic mice. We determine numbers of OVA-specific T effector cells and T regulatory cells in the adoptively transferred mice and in control mice that receive untreated resting B cells alone by flow cytometry (Foxp3). We further determine if these T regulatory cells mediate immunosuppressive activities by using proliferation assay in vitro and by in vivo prevention of immune response against challenge with OVA + adjuvant. This study will provide basis to develop approaches to induce antigen-specific T regulatory cells to treat inflammatory diseases such as allergy and autoimmune diseases.
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Semple, Kenrick, Yu Yu, Dapeng Wang, Claudio Anasetti, and Xue-Zhong Yu. "Efficient and Selective Prevention of Graft-Versus-Host Disease by Ag-Specific Induced Regulatory T Cells In Mice." Blood 116, no. 21 (November 19, 2010): 3745. http://dx.doi.org/10.1182/blood.v116.21.3745.3745.
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Abstract Abstract 3745 Naturally occurring regulatory T cells (nTregs) suppress the development of graft-versus-host disease (GVHD). The non-selective suppression against tumor associated antigens in some models severely dampened our enthusiasm for the application of nTregs in the control of GVHD after allogeneic hematopoietic cell transplantation (HCT). In this study, we used an alternative strategy to generate antigen-specific, induced Tregs (iTregs), and tested their potential in the prevention of GVHD in murine model of myeloablative BMT. CD4+CD25+Foxp3+ iTregs generated from OT-II TCR transgenic mice specific for OVA target antigen efficiently prevented GVHD induced by polyclonal T effector cells (Teffs) in allogeneic recipients that express OVA protein but not in those that do not express OVA. The efficacy of these antigen-specific iTregs was significantly higher than polyclonal iTregs in preventing GVHD. As controls, OT-II CD4+Foxp3− cells had no effect on GVHD development in OVA− recipients and exacerbated GVHD in OVA+ recipients when transplanted together with polyclonal Teffs. Mechanistically, OT-II iTregs expanded extensively, and significantly suppressed expansion and infiltration of Teffs in OVA+ recipients. In sharp contrast, OT-II iTregs failed to expand and had no effect on Teffs in OVA− recipients. These results reveal the therapeutic potential of TGFβ-induced, antigen-specific iTregs to prevent GVHD efficiently and selectively. Disclosures: No relevant conflicts of interest to declare.
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Bagavant, Harini, Yogesh Scindia, Seshagiri Nandula, and Umesh Deshmukh. "Role of T cell mediated inflammation in lupus-like glomerulonephritis (GN) (93.40)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 93.40. http://dx.doi.org/10.4049/jimmunol.184.supp.93.40.
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Abstract Renal involvement in lupus is characterized by glomerular immune complexes, acute proliferative GN and progressive renal failure. To investigate the pathogenic role of T cells in renal lupus, an antigen-specific model of GN was established. A novel, anti-α8 integrin immunoliposomal delivery system (α8ILs) was designed for targeted delivery to the renal glomerulus. Ovalbumin loaded α8ILs (ova-α8ILs) were injected i.v. into C57BL/6 mice leading to a rapid delivery of ova in the glomerular mesangium. Injection of ova-α8ILs followed by ova-reactive transgenic OT2 cells activated in vitro, resulted in GN. On day 7 after injection, the renal cortex showed T cell, macrophage and dendritic cell infiltration. To mimic lupus GN, mice were injected with ova-α8ILs and mouse anti-ova serum forming glomerular immune complexes. This was followed by injection of naïve CSFE labeled OT2 cells. Two days after cell transfer, mice with glomerular immune complexes showed dividing OT2 cells preferentially in renal lymph nodes compared to mice given ova-α8ILs alone. Recently, macrophage infiltration into the renal interstitium has been identified as the harbinger of renal failure. Our data suggest that glomerular antigen-specific T cell infiltration may be sufficient for recruitment of macrophages into the renal cortex and the onset of progressive renal inflammation. In addition, glomerular immune complexes lead to a rapid, local activation of glomerular antigen reactive T cells.
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Saumyaa, Saumyaa, Swadhinya Arjunaraja, Raul Torres, and Clifford Snapper. "Regulation of T-cell dependent IgG response to soluble protein antigens in the presence and absence of intact bacteria (43.9)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 43.9. http://dx.doi.org/10.4049/jimmunol.188.supp.43.9.
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Abstract During bacterial infections the immune system encounters Ags associated with the intact bacterium simultaneously with those that are released in soluble form, although the immunologic consequences of this on IgG responses to the latter are unknown. We previously demonstrated that intact inactivated Streptococcus pneumoniae (strain R36A) inhibits IgG responses to co-immunized soluble Ags. We investigated the mechanism of this inhibition using intact R36A and soluble chicken ovalbumin (OVA). Using the i.v. route, no inhibition was observed if R36A was given 24h before or after immunization with OVA, indicating an early and transient inhibitory effect. This inhibition could be partially overcome by co-immunization with a strong adjuvant. Using transgenic OVA-specific CD4+ T cells, we observed that R36A had no significant effect on OVA-induced T-cell activation (24h) or generation of regulatory T cells (d7), and only a modest effect on proliferation (48-96h). However, R36A mediated a significant reduction in PD1+GL7+ OVA-specific T cells (germinal center T follicular helper cells) suggesting an inhibitory effect on the GC reaction. Of note, co-immunization of OVA with either intact inactivated Streptococcus agalactiae or Neisseria meningitidis resulted in a significant enhancement of the OVA-specific IgG response. These results strongly suggest that Streptococcus pneumoniae may uniquely express a component capable of inhibiting humoral immune responses to soluble antigens.
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Zhang, Ai-Hong, and David Scott. "Antigen-specific B cells are not required for soluble OVA protein induced T-cell tolerance through i.v. route (65.8)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 65.8. http://dx.doi.org/10.4049/jimmunol.188.supp.65.8.
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Abstract Intravenous exposure to soluble proteins can lead to antigen-specific immune tolerance. Moreover, resting B cells have been shown to be tolerogenic antigen-presenting cells (APC) in vivo. However, it is still not clear whether this APC function is fulfilled by the rare antigen-specific B cells or the abundant antigen non-specific B cells. To address this, we used soluble chicken ovalbumin (OVA) as a model antigen and employed B-cell receptor (BCR) transgenic mice (8.18C5 Tg) of C57BL6 (B6) background. In the homozygous 8.18C5 Tg mice, ~97% of peripheral B cells contain recombined immunoglobulin heavy chain specific for non-related myelin oligodendrocyte glycoprotein. As expected, a single i.v. dose of soluble OVA in wt B6 mice induced significant B+T cell tolerance. The 8.18C5 Tg mice immunized with OVA+CFA failed to produce any detectible anti-OVA antibody response, confirming the lack of OVA-specific endogenous B cells in these mice. Importantly, pretreatment of the 8.18C5 Tg mice with 25µg soluble OVA i.v. also resulted in profound T-cell tolerance upon OVA+CFA challenge a week later. Since antigen non-specific B cells can present processed antigen after soluble protein exposure in vivo, our results support the notion that antigen non-specific resting B cells in the steady state may participate in the peripheral tolerance to self proteins.
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Shalaby, Karim H., Gregory S. Whitehead, Seddon Y. Thomas, and Donald N. Cook. "Chronic antigen-specific T helper 17 inflammatory responses in the lungs require persistent adjuvant exposure to be sustained." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 133.6. http://dx.doi.org/10.4049/jimmunol.196.supp.133.6.
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Abstract Allergic asthma is characterized by exaggerated lung T helper 2 (Th2) and Th17 responses which require signals that stimulate the innate immune system, provided by exposure to environmental adjuvants with an allergen. Once airway disease has developed, it is unclear as to whether the same mechanisms that initiated the disease remain important in sustaining it. We investigated the contribution of persistent innate danger signals in sustaining a chronic antigen-specific Th17 cell response. Animals were sensitized and challenged acutely by aspiration of ovalbumin (OVA) with different adjuvants, including house dust extract (HDE). They were then challenged for a further 5 weeks with OVA alone or OVA + adjuvant to test whether the adjuvant becomes redundant in sustaining airway inflammation once it has already been established. Removal of the adjuvant during the chronic challenges resulted in the animals displaying minimal airway inflammation, whereas continuous challenge with adjuvant and OVA caused significant inflammation. HDE was particularly potent at promoting airway neutrophilia, lymphocytosis and greater IL-17A production from lung explants restimulated ex vivo with OVA, suggesting that persistent exposure to this adjuvant amplified the antigen-specific Th17 response. Furthermore, CD4+ cells from OVA-receptor transgenic (OT-II) IL-17A-fate mapping mice were differentiated under Th17 polarizing conditions and adoptively transferred to recipients which were then challenged with either OVA alone, OVA + HDE or HDE alone. Persistent exposure to HDE and OVA, compared to either one alone, amplified the lung antigen-specific memory Th17 response, independently of the enzymatic activity of HDE but rather via TLR4 signaling.
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Wang, Lixin, Eric Dobrzynski, Alexander Schlachterman, Ou Cao, and Roland W. Herzog. "Systemic protein delivery by muscle-gene transfer is limited by a local immune response." Blood 105, no. 11 (June 1, 2005): 4226–34. http://dx.doi.org/10.1182/blood-2004-03-0848.
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Abstract Adeno-associated viral (AAV) vectors have been successfully used for therapeutic expression of systemic transgene products (such as factor IX or erythropoietin) following in vivo administration to skeletal muscle of animal models of inherited hematologic disorders. However, an immune response may be initiated if the transgene product represents a neoantigen. Here, we use ovalbumin (OVA) as a model antigen and demonstrate immune-mediated elimination of expression on muscle-directed AAV-2 gene transfer. Administration to immune competent mice resulted in transient systemic OVA expression. Within 10 days, OVA-specific T-helper cells had been activated in draining lymph nodes, an inflammatory immune response ensued, and OVA-expressing muscle fibers were destroyed by a cytotoxic CD8+ T-cell response. Use of a muscle-specific promoter did not prevent this immune response. Adoptively transferred CD4+ cells transgenic for a T-cell receptor specific to OVA peptide-major histocompatibility complex class II showed antigen-specific, vector dose-dependent proliferation confined to the draining lymph nodes of AAV-OVA–transduced muscle within 5 days after gene transfer and subsequently participated in lymphocytic infiltration of transduced muscle. This study documents that a local immune response limits sustained expression of a secreted protein in muscle gene transfer, a finding that may have consequences for design of clinical protocols.
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Haneda, K., K. Sano, G. Tamura, T. Sato, S. Habu, and K. Shirato. "TGF-beta induced by oral tolerance ameliorates experimental tracheal eosinophilia." Journal of Immunology 159, no. 9 (November 1, 1997): 4484–90. http://dx.doi.org/10.4049/jimmunol.159.9.4484.
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Abstract Induction of peripheral tolerance is one of the feasible approaches for the control of autoimmunities and allergies. Therapeutic applications of oral tolerance to autoimmunities are in progress both experimentally and clinically, while those to allergies have been poorly investigated. We examined the induction of CD4+ T cells with suppressive properties by oral tolerance and the mechanism by which these cells down-regulated Ag-induced eosinophilia in the trachea. Feeding of mice transgenic for anti-OVA TCR with high doses of OVA inhibited the airway eosinophilic inflammation induced by the intratracheally administered Ag. This inhibition reflected the mechanism of active suppression, since the inhibitory effect was adoptively transferred by splenic CD4+ T cells from the transgenic mice fed with high doses of OVA. The Ag specificity of the suppressor T cells was documented by the failure of spleen cells from mice that were orally tolerant of OVA to suppress irrelevant Ag, KLH-specific airway eosinophilic inflammation. The suppressive effect of the transferred T cells on eosinophil recruitment was neutralized by anti-TGF-beta mAb, but not anti-IFN-gamma mAb, indicating that the suppression is due to the inhibitory effect by secreted TGF-beta, but not to the dominance of the transferred Th1 cells over Th2 cells. This is the first study to reveal a link between oral tolerance and the regulation of Th2-mediated experimental tracheal eosinophilia through TGF-beta. Our experimental model suggests possible therapeutic applications of oral tolerance for the treatment of allergic disorders such as bronchial asthma.
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Bonifaz, Laura, David Bonnyay, Karsten Mahnke, Miguel Rivera, Michel C. Nussenzweig, and Ralph M. Steinman. "Efficient Targeting of Protein Antigen to the Dendritic Cell Receptor DEC-205 in the Steady State Leads to Antigen Presentation on Major Histocompatibility Complex Class I Products and Peripheral CD8+ T Cell Tolerance." Journal of Experimental Medicine 196, no. 12 (December 16, 2002): 1627–38. http://dx.doi.org/10.1084/jem.20021598.
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To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal αDEC-205 antibody, was presented by CD11c+ lymph node DCs, but not by CD11c− cells, to OVA-specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When αDEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4–48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of αDEC-205:OVA to DCs in the steady state initially induced 4–7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together with αDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic αCD40 antibody produced large amounts of interleukin 2 and interferon γ, acquired cytolytic function in vivo, emigrated in large numbers to the lung, and responded vigorously to OVA rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation.
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Daniel, Benjamin J., AiJie Liu, Srilakshmi Pandeswara, Sara M. Ludwig, Michael J. Brumlik, Kristina M. Church, Mark J. Kious, and Tyler J. Curiel. "Interleukin-12 is dispensable for functional interferon (IFN)-gamma producing CD8+ cytotoxic T cells in Toxoplasma gondii infection (133.28)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 133.28. http://dx.doi.org/10.4049/jimmunol.182.supp.133.28.
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Abstract Interleukin (IL)-12 is a proinflammatory cytokine generally regarded as a master regulator of type 1 T cell mediated immunity against intracellular pathogens, including T. gondii and cancers. A critical measure of IL-12 activity is its ability to induce IFN-γ production by NK and T cells. Using a transgenic T. gondii expressing ovalbumin (OVA), we show here that by flow cytometry analysis T. gondii-OVA infected BL6 IL-12-/- mice generate OVA-pentamer+CD8+ T cells similar to WT and surprisingly, T. gondii-infected IL-12-/- mice produce more IFN-γ +CD8+ T cells than T. gondii-infected WT mice (avg 9.6% in IL-12-/- vs 3.7% in WT). We confirmed that function of OVA-specific CD8+ T cells in IL-12-/- was comparable to BL6 WT using an in vivo OVA+ target lysis assay. As expected, IFN-γ +CD4+ T cells decreased from an avg 29% to 9% in WT mice compared to IL-12-/- mice respectively when infected with T. gondii. These results demonstrate a novel IL-12-independent pathway to CD8+ CTL that may be less dependent of CD4+ T cell help than previously thought.
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Yamashita, Naomi, Hiroyuki Tashimo, Hirofumi Ishida, Yukiko Matsuo, Hidekazu Tamauchi, Masazumi Terashima, Ikuo Yoshiwara, Sonoko Habu, and Ken Ohta. "Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 6 (June 2006): L1045—L1051. http://dx.doi.org/10.1152/ajplung.00195.2005.
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The pathophysiological characteristics of bronchial asthma consist of chronic inflammation of airways, airway hyperresponsiveness, and bronchoconstriction. Studies have shown that T helper type 2 (Th2) cytokines produced by both T cells and mast cells in the airway contribute substantially to the initiation of inflammation in both experimental and human bronchial asthma. GATA-3 is a transcription factor essential to the production of Th2 cytokines by T lymphocytes. To clarify the role of GATA-3-expressing T cells in the pathophysiology of bronchial asthma, we utilized transgenic (Tg) mice carrying the GATA-3 gene and the ovalbumin (OVA)-specific T cell receptor gene (GATA-3-Tg/OVA-Tg). Mice were intranasally administrated OVA without systemic immunization. Airway responses were analyzed with noninvasive and invasive whole body plethysmographs. GATA-3-Tg/OVA-Tg mice exhibited significantly higher IL-13 and IL-4 protein expression in the airway. Although there were no differences in the types of infiltrating cells between GATA-3-Tg/OVA-Tg and GATA-3-non-Tg/OVA-Tg mice and no significant increase in IgE level in either group compared with nontreated mice, the response after ACh inhalation was significantly elevated in GATA-3-Tg/OVA-Tg on the seventh day of intranasal treatment with OVA. This hyperresponsiveness was inhibited by 5-lipoxygenase inhibitor and IL-13 neutralization, suggesting that airway responses were induced through IL-13 and leukotriene pathway. In conclusion, airway hyperresponsiveness, a characteristic of bronchial asthma, is regulated at the level of GATA-3 transcription by T lymphocytes in vivo.
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Marth, Thomas, Martin Zeitz, Bjorn R. Ludviksson, Warren Strober, and Brian L. Kelsall. "Extinction of IL-12 Signaling Promotes Fas-Mediated Apoptosis of Antigen-Specific T Cells." Journal of Immunology 162, no. 12 (June 15, 1999): 7233–40. http://dx.doi.org/10.4049/jimmunol.162.12.7233.
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Abstract In previous studies we have shown that peripheral tolerance achieved by high dose feeding of OVA to intact OVA-TCR transgenic mice was enhanced when endogenous IL-12 was neutralized simultaneously. To generalize this phenomenon, in the present study we investigated the tolerogenic mechanisms underlying the blockade of IL-12 signaling following oral and systemic Ag delivery. We found that the numbers of Ag-specific T cells in several lymphoid organs were significantly reduced due to T cell apoptosis following oral OVA or systemic OVA administration when combined with anti-IL-12 injection, but there was no decrease in T cell numbers for OVA-fed, OVA-injected, or anti-IL-12 alone-treated mice compared with those in untreated control mice. In addition, mostly Fas+ T cells were subject to apoptotic deletion in the OVA- plus anti-IL-12-treated groups, and an enhanced cell death of T cells upon OVA restimulation in vitro could be partially reversed by blockade of the Fas/Fas ligand interaction. Finally, in a murine model of superantigen-driven T cell expansion and deletion, we observed no deletional effects of anti-IL-12 treatment on CD4+ cells in Fas-deficient (MRL/lpr) mice, but did find these effects in MRL wild-type mice. In summary, our data suggest that in the course of Ag-induced cell proliferation of Th1 cells, signaling through IL-12 is required to prevent an induction of Fas-mediated apoptosis. Thus, the use of anti-IL-12 may be potentially useful in modulating peripheral immune responses by promotion of Fas-mediated cell death.
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Lee, Hyang Mi, and Chyi-Song Hsieh. "The role of TCR affinity in thymic regulatory T cell development (148.9)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 148.9. http://dx.doi.org/10.4049/jimmunol.186.supp.148.9.
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Abstract TCR-dependent generation of natural Foxp3+ CD4+ regulatory T cells (Treg) in the thymus is essential for maintaining self-tolerance. Although a simply affinity model of self-antigen recognition is widely accepted as governing thymic Treg development, it is poorly substantiated experimentally. To address the mechanism by which TCR interactions with peptide:MHC complex result in Treg development, we are analyzing the ability of a variety of TCRs to facilitate Treg development due to interactions with OVA(323-339) expressed via the RIP-mOVA transgene. To obtain TCRs with varying reactivity to OVA, we sequenced TCR-alpha chains of proliferating CD4+ T cells from DO11 TCR-beta transgenic mice stimulated in vitro with OVA peptide. OVA reactivity was confirmed by retroviral transduction of individual TCRs into a hybridoma cell line expressing an NFAT-GFP reporter for TCR activation. Approximately 9 TCRs have thus far been obtained that show up to 1000-fold differences in sensitivity to OVA in vitro. Sensitivity to OVA appeared to correlate with the ability to facilitate RIP-mOVA dependent Treg development. Using DO11-alpha-beta TCR as a reference point for TCR-cognate peptide interaction, one TCR with a 1,000 fold lower reactivity to OVA was unable to facilitate Treg development, whereas TCRs within 100-fold sensitivity were capable. Thus, these preliminary data allow us to begin to quantify the nature of TCR interactions with peptide:MHC required for Treg selection.
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Kurts, Christian, William R. Heath, Hiroshi Kosaka, Jacques F. A. P. Miller, and Francis R. Carbone. "The Peripheral Deletion of Autoreactive CD8+ T Cells Induced by Cross-presentation of Self-antigens Involves Signaling through CD95 (Fas, Apo-1)." Journal of Experimental Medicine 188, no. 2 (July 20, 1998): 415–20. http://dx.doi.org/10.1084/jem.188.2.415.
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Recently, we demonstrated that major histocompatibility complex class I–restricted cross-presentation of exogenous self-antigens can induce peripheral T cell tolerance by deletion of autoreactive CD8+ T cells. In these studies, naive ovalbumin (OVA)-specific CD8+ T cells from the transgenic line OT-I were injected into transgenic mice expressing membrane-bound OVA (mOVA) under the control of the rat insulin promoter (RIP) in pancreatic islets, kidney proximal tubules, and the thymus. Cross-presentation of tissue-derived OVA in the renal and pancreatic lymph nodes resulted in activation, proliferation, and then the deletion of OT-I cells. In this report, we investigated the molecular mechanisms underlying this form of T cell deletion. OT-I mice were crossed to tumor necrosis factor receptor 2 (TNFR2) knockout mice and to CD95 (Fas, Apo-1) deficient mutant lpr mice. Wild-type and TNFR2-deficient OT-I cells were activated and then deleted when transferred into RIP-mOVA mice, whereas CD95-deficient OT-I cells were not susceptible to deletion by cross-presentation. Furthermore, cross-presentation led to upregulation of the CD95 molecule on the surface of wild-type OT-I cells in vivo, consistent with the idea that this is linked to rendering autoreactive T cells susceptible to CD95-mediated signaling. This study represents the first evidence that CD95 is involved in the deletion of autoreactive CD8+ T cells in the whole animal.
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Vermaelen, Karim Y., Ines Carro-Muino, Bart N. Lambrecht, and Romain A. Pauwels. "Specific Migratory Dendritic Cells Rapidly Transport Antigen from the Airways to the Thoracic Lymph Nodes." Journal of Experimental Medicine 193, no. 1 (December 27, 2000): 51–60. http://dx.doi.org/10.1084/jem.193.1.51.
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Antigen transport from the airway mucosa to the thoracic lymph nodes (TLNs) was studied in vivo by intratracheal instillation of fluorescein isothiocyanate (FITC)-conjugated macromolecules. After instillation, FITC+ cells with stellate morphology were found deep in the TLN T cell area. Using flow cytometry, an FITC signal was exclusively detected in CD11cmed-hi/major histocompatibility complex class II (MHCII)hi cells, representing migratory airway-derived lymph node dendritic cells (AW-LNDCs). No FITC signal accumulated in lymphocytes and in a CD11chiMHCIImed DC group containing a CD8αhi subset (non–airway-derived [NAW]-LNDCs). Sorted AW-LNDCs showed long MHCIIbright cytoplasmic processes and intracytoplasmatic FITC+ granules. The fraction of FITC+ AW-LNDCs peaked after 24 h and had reached baseline by day 7. AW-LNDCs were depleted by 7 d of ganciclovir treatment in thymidine kinase transgenic mice, resulting in a strong reduction of FITC-macromolecule transport into the TLNs. Compared with intrapulmonary DCs, AW-LNDCs had a mature phenotype and upregulated levels of MHCII, B7-2, CD40, and intracellular adhesion molecule (ICAM)-1. In addition, sorted AW-LNDCs from FITC-ovalbumin (OVA)–instilled animals strongly presented OVA to OVA-TCR transgenic T cells. These results validate the unique sentinel role of airway DCs, picking up antigen in the airways and delivering it in an immunogenic form to the T cells in the TLNs.