scholarly journals MHCII glycosylation modulates Bacteroides fragilis carbohydrate antigen presentation

2011 ◽  
Vol 208 (5) ◽  
pp. 1041-1053 ◽  
Author(s):  
Sean O. Ryan ◽  
Jason A. Bonomo ◽  
Fan Zhao ◽  
Brian A. Cobb
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bacteroides Fragilis ◽  
Carbohydrate Antigen ◽  
Activated T Cells ◽  
Mhc Molecules

N-linked glycans are thought to protect class II major histocompatibility complex (MHC) molecules (MHCII) from proteolytic cleavage and assist in arranging proteins within the immune synapse, but were not thought to directly participate in antigen presentation. Here, we report that antigen-presenting cells (APCs) lacking native complex N-glycans showed reduced MHCII binding and presentation of the T cell activating glycoantigen (GlyAg) polysaccharide A from Bacteroides fragilis but not conventional peptides. APCs lacking native N-glycans also failed to mediate GlyAg-driven T cell activation but activated T cells normally with protein antigen. Mice treated with the mannosidase inhibitor kifunensine to prevent the formation of complex N-glycans were unable to expand GlyAg-specific T cells in vivo upon immunization, yet adoptive transfer of normally glycosylated APCs into these animals overcame this defect. Our findings reveal that MHCII N-glycosylation directly impacts binding and presentation of at least one class of T cell–dependent antigen.

NFATc3 regulates the transcription of genes involved in T-cell activation and angiogenesis

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 795-803 ◽  
Author(s):  
Katia Urso ◽  
Arantzazu Alfranca ◽  
Sara Martínez-Martínez ◽  
Amelia Escolano ◽  
Inmaculada Ortega ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Target Genes ◽  
Gene Knockout ◽  
Activated T Cells ◽  
Knock Down ◽  
And Function

Abstract The nuclear factor of activated T cells (NFAT) family of transcription factors plays important roles in many biologic processes, including the development and function of the immune and vascular systems. Cells usually express more than one NFAT member, raising the question of whether NFATs play overlapping roles or if each member has selective functions. Using mRNA knock-down, we show that NFATc3 is specifically required for IL2 and cyclooxygenase-2 (COX2) gene expression in transformed and primary T cells and for T-cell proliferation. We also show that NFATc3 regulates COX2 in endothelial cells, where it is required for COX2, dependent migration and angiogenesis in vivo. These results indicate that individual NFAT members mediate specific functions through the differential regulation of the transcription of target genes. These effects, observed on short-term suppression by mRNA knock-down, are likely to have been masked by compensatory effects in gene-knockout studies.

scholarly journals Abortive Proliferation of Rare T Cells Induced by Direct or Indirect Antigen Presentation by Rare B Cells In Vivo

1998 ◽  
Vol 187 (10) ◽  
pp. 1611-1621 ◽  
Author(s):  
Sarah E. Townsend ◽  
Christopher C. Goodnow
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Antigen Presentation ◽  
Cell Fate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Antigen Presenting

Antigen-specific B cells are implicated as antigen-presenting cells in memory and tolerance responses because they capture antigens efficiently and localize to T cell zones after antigen capture. It has not been possible, however, to visualize the effect of specific B cells on specific CD4+ helper T cells under physiological conditions. We demonstrate here that rare T cells are activated in vivo by minute quantities of antigen captured by antigen-specific B cells. Antigen-activated B cells are helped under these conditions, whereas antigen-tolerant B cells are killed. The T cells proliferate and then disappear regardless of whether the B cells are activated or tolerant. We show genetically that T cell activation, proliferation, and disappearance can be mediated either by transfer of antigen from antigen-specific B cells to endogenous antigen-presenting cells or by direct B–T cell interactions. These results identify a novel antigen presentation route, and demonstrate that B cell presentation of antigen has profound effects on T cell fate that could not be predicted from in vitro studies.

T cell-T cell activation in multiple sclerosis

1997 ◽  
Vol 3 (4) ◽  
pp. 238-242 ◽  
Author(s):  
JW Lindsey ◽  
RH Kerman ◽  
JS Wolinsky
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Viral Infections ◽  
Activated T Cells ◽  
In Vitro Proliferation

Activated T cells are able to stimulate proliferation in resting T cells through an antigen non-specific mechanism. The in vivo usefulness of this T cell-T cell activation is unclear, but it may serve to amplify immune responses. T cell-T cell activation could be involved in the well-documented occurrence of multiple sclerosis (MS) exacerbations following viral infections. Excessive activation via this pathway could also be a factor in the etiology of MS. We tested the hypothesis that excessive T cell-T cell activation occurs in MS patients using in vitro proliferation assays comparing T cells from MS patients to T cells from controls. When tested as responder cells, T cells from MS patients proliferated slightly less after stimulation with previously activated cells than T cells from controls. When tested as stimulator cells, activated cells from MS patients stimulated slightly more non-specific proliferation than activated cells from controls. Neither of these differences were statistically significant We conclude that T cell proliferation in response to activated T cells is similar in MS and controls.

Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2181-2190 ◽  
Author(s):  
Maria Paola Martelli ◽  
Huamao Lin ◽  
Weiguo Zhang ◽  
Lawrence E. Samelson ◽  
Barbara E. Bierer
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Adapter Protein ◽  
Activated T Cells

Abstract Activation of T cells can be initiated through cell surface molecules in addition to the T-cell receptor-CD3 (TCR-CD3) complex. In human T cells, ligation of the CD2 molecule by mitogenic pairs of anti-CD2 monoclonal antibodies activates T cells via biochemical signaling pathways similar but not identical to those elicited on TCR engagement. This study describes a key role for the p36/38 membrane adapter protein linker for T cell activation (LAT) in CD2-mediated T-cell activation. Following ligation of CD2 on the surface of the Jurkat T-cell line and human purified T cells, LAT was tyrosine phosphorylated and shown to associate in vivo with a number of other tyrosine phosphorylated proteins including PLCγ-1, Grb-2, and SLP-76. Using Jurkat cell lines deficient in ZAP70/Syk (P116) or LAT (ANJ3) expression, CD2-dependent PLCγ-1 and SLP-76 tyrosine phosphorylation required expression both of ZAP70 or Syk and of LAT. As predicted, the absence of either LAT or ZAP70/Syk kinases correlated with a defect in the induction of nuclear factor of activated T cells (NFAT) transcriptional activity, activation of the interleukin-2 promoter, and ERK phosphorylation following CD2 stimulation. These data suggest that LAT is an adapter protein important for the regulation of CD2-mediated T-cell activation.

Signaling via LAT (linker for T-cell activation) and Syk/ZAP70 is required for ERK activation and NFAT transcriptional activation following CD2 stimulation

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2181-2190 ◽  
Author(s):  
Maria Paola Martelli ◽  
Huamao Lin ◽  
Weiguo Zhang ◽  
Lawrence E. Samelson ◽  
Barbara E. Bierer
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Adapter Protein ◽  
Activated T Cells

Activation of T cells can be initiated through cell surface molecules in addition to the T-cell receptor-CD3 (TCR-CD3) complex. In human T cells, ligation of the CD2 molecule by mitogenic pairs of anti-CD2 monoclonal antibodies activates T cells via biochemical signaling pathways similar but not identical to those elicited on TCR engagement. This study describes a key role for the p36/38 membrane adapter protein linker for T cell activation (LAT) in CD2-mediated T-cell activation. Following ligation of CD2 on the surface of the Jurkat T-cell line and human purified T cells, LAT was tyrosine phosphorylated and shown to associate in vivo with a number of other tyrosine phosphorylated proteins including PLCγ-1, Grb-2, and SLP-76. Using Jurkat cell lines deficient in ZAP70/Syk (P116) or LAT (ANJ3) expression, CD2-dependent PLCγ-1 and SLP-76 tyrosine phosphorylation required expression both of ZAP70 or Syk and of LAT. As predicted, the absence of either LAT or ZAP70/Syk kinases correlated with a defect in the induction of nuclear factor of activated T cells (NFAT) transcriptional activity, activation of the interleukin-2 promoter, and ERK phosphorylation following CD2 stimulation. These data suggest that LAT is an adapter protein important for the regulation of CD2-mediated T-cell activation.

scholarly journals Selective immunosuppression by administration of major histocompatibility complex (MHC) class II-binding peptides. I. Evidence for in vivo MHC blockade preventing T cell activation.

1992 ◽  
Vol 175 (5) ◽  
pp. 1345-1352 ◽  
Author(s):  
J C Guéry ◽  
A Sette ◽  
J Leighton ◽  
A Dragomir ◽  
L Adorini
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Class Ii ◽  
Specific Class ◽  
Binding Peptide

Draining lymph node cells (LNC) from mice immunized with hen egg white lysozyme (HEL) display at their surface antigen-MHC complexes able to stimulate, in the absence of any further antigen addition, HEL peptide-specific, class II-restricted T cell hybridomas. Chloroquine addition to these LNC cultures fails to inhibit antigen presentation, indicating that antigenic complexes of class II molecules and HEL peptides are formed in vivo. MHC class II restriction of antigen presentation by LNC from HEL-primed mice was verified by the use of anti-class II monoclonal antibodies. Coinjection of HEL and the I-Ak-binding peptide HEL 112-129 in mice of H-2k haplotype inhibits the ability of LNC to stimulate I-Ak-restricted, HEL 46-61-specific T cell hybridomas. Similar results are obtained in mice coinjected with the HEL peptides 46-61 and 112-129. Inhibition of T hybridoma activation can also be observed using as antigen-presenting cells irradiated, T cell-depleted LNC from mice coinjected with HEL 46-61 and HEL 112-129, ruling out the possible role of either specific or nonspecific suppressor T cells. Inhibition of T cell proliferation is associated with MHC-specific inhibition of antigen presentation and with occupancy by the competitor of class II binding sites, as measured by activation of peptide-specific T cell hybridomas. These results demonstrate that administration of MHC class II binding peptide competitors selectively inhibits antigen presentation to class II-restricted T cells, indicating competitive blockade of class II molecules in vivo.

Phenotypic and Functional Characterization Of a Novel Immature Hematopoietic Myeloid Suppressive Progenitor Cells Mobilized By G-CSF. Application To Gvhd Treatment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4476-4476
Author(s):  
Marie T Rubio ◽  
Maud D'Aveni ◽  
Tereza Coman ◽  
Julien Rossignol ◽  
Julie Bruneau ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Acute Gvhd ◽  
Activated T Cells ◽  
Stem Cell Graft ◽  
Alloreactive T Cell

Background Myeloid derived suppressive cells (MDSCs) represent a heterogeneous population of cells endowed with immunosuppressive properties. They have been first described in the tumor microenvironment. Some mature MDSCs either induced by GM-CSF and IL-13 (Highfill et al., Blood 2010) or mobilized by G-CSF (Joo et al., Immunology 2009) have been reported to control experimental GVHD by inhibiting alloreactive T cell proliferation. We describe here the existence in mice and humans of a not yet characterized population of GCSF-mobilized hematopoïetic cells with phenotypic characteristics of immature MDSCs (called therefore pro-MDSCs) that can inhibit GVHD by a distinct mechanism than those described with classical mature MDSCs. Methods In the C57BL6 mouse and human, G-CSF mobilized MDSCs were collected and analyzed in the spleen and PBSC using several antibodies directed against various markers of maturity, lineage specific antigens and chemokine receptors. Depending on the expression of maturity antigens various population were sorted. In vitro, functions of sorted MDSC were analyzed by co-cultures with T cells activated either by anti-CD3 and CD28 mAbs or allogeneic dendritic cells. In vivo, the effect of various population of MDSCs on GVHD was assessed either by the transfer of murine C57BL6 (H-2b) cells (2x106 splenic T cells + 5x106 T depleted bone marrow cells +/- 0.5x106 MDSC subtypes) into lethally irradiated BALB/c (H-2d) recipients or by injecting 2x105 human pro-MDSCs with 2.5x106 human PBMC into 2 Gy irradiated Nod/SCID/gammac-/- mice. In 19 allografted patients, proportions of MDSC subpopulations contained in the peripheral stem cell graft were correlated to the occurrence of acute GVHD and to the post-transplant peripheral blood levels of conventional proliferating T cells and CD4+ CD25+ CD127low reguatory T cells (T regs). Results In the G-CSF mobilized cells, immature Lin- Sca1high cKithigh CD34+ CX3CR1+ CD16/32+ CD11b+ Ly6C+ and Lin- CD34+ HLA-DR- CD33high CD11blow CD14+ cell populations were identified in mice spleen and human PBSC, respectively. Because the pattern of maturity antigen expression, these populations were named pro-MDSCs. The mature MDSC counterparts shared the same differentiation phenotype without the markers of maturity. In vitro, both murine and human pro-MDSCs, but not the corresponding mature MDSCs, could inhibit the proliferation and induced the apoptosis of activated T cells (p<0,001). The inhibition of T cell activation by pro-MDSCs required IFN-gamma produced by activated T-cells and the production of NO by pro-MDSCs in response to IFN-gamma. NO suppressed T-cell functions through impaired responses to IL2 and induction of apoptosis. In vivo, in the C57BL6 to BALB/c GVHD model, the administration of murine pro-MDSCs significantly reduced the development of clinical and histological GVHD signs as compared to allografted mice without pro-MDSCs or with GCSF-mobilized mature MDSCs (p=0,03). Murine pro-MDSCs could migrate to site of allo-priming and induced the apoptosis of allogeneic T cells when compared to mice allografted without pro-MDSCs (p<0,01). In mice that had received pro-MDSCs, we observed that apoptotic T cells could be engulfed by phagocytes and that those phagocytes produced high levels of cytokines (IL-10, TGF-beta), which was associated with increased induced CD4+CD25+Foxp3+ T regs leading to the induction of tolerance. These observations were not seen in mice allografted without pro-MDSCs (p<0,05). Human pro-MDSCs could protect all xeno-grafted Nod/SCID/gamma c-/- mice from GVHD mortality as compared to 100% GVHD lethality in controlled xeno-grafted mice without pro-MDSCs (p<0,001). Allografted patients having received a stem cell graft containing levels of Pro-MDSCs >10% of the CD34+ fraction had a significantly reduced risk of developing grade II-IV acute GVHD (p= 0,04) and reduced numbers of proliferating conventional T cells but higher numbers of T regs in the peripheral blood on days 15 and 30 post-HSCT (p<0.05). No correlation between the occurrence of acute GVHD and the proportions of mature MDSCs contained in the graft was observed. Conclusion We have characterized a new homogeneous population of G-CSF mobilized immature MDSCs, which has been named pro-MDSC that can regulate alloreactive T cell activation in vitro and in vivo by inducing tolerance with potential therapeutic application in allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

Hepatic AAV Gene Transfer of Cytoplasmic Transgene Induces Transgene Product-Specific T Cell Activation Initially in the Liver and Celiac Lymph Node Preceding Treg Induction

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3241-3241
Author(s):  
Roland W. Herzog ◽  
George Q. Perrin
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Gene Transfer ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Lymphoid Organs ◽  
Activated T Cells

Abstract In several published studies, we have shown induction of immune tolerance to coagulations factors by hepatic gene transfer to animals with hemophilia. Tolerance induction is influenced by a number of complex factors, most notably T cell activation and induction of antigen-specific CD4+CD25+FoxP3+ regulatory T cells (Treg). We sought to better understand antigen presentation to CD4+ T cells and the dynamics of the resulting T cell response. To characterize the interaction of adeno-associated virus (AAV) antigen expression in the liver with immune cells, we used an AAV8 vector, which have a high tropism for murine liver, expressing cytoplasmic ovalbumin (AAV8-Cyto-Ova) from the EF1α promoter. Use of AAV8-Cyto-Ova allowed us to eliminate effects from systemic antigen delivery. Vector was injected into the tail vein of DO11.10-transgenic RAG-/- mice, which contain exclusively Ova-specific CD4+ T cells and lack Treg. AAV8-Cyto-Ova caused upregulation of the very early activation marker CD69 on the CD4+ T cells as early as 2 weeks after gene transfer, with induced Treg emerging at about 3 weeks. CD69+CD4+ T cells were first observed in greatest numbers in the liver and celiac lymph node (LN), one of the liver-draining LN. This T cell activation persisted for several weeks. To better define the sites of T cell activation, we used the compound FTY720, which is an agonist of sphingosine-1-phosphate receptors and prevents migration of lymphocytes but does not alter T cell function. Two weeks after AAV8-Cyto-Ova, FTY720 sequestered activated T cells mostly in the liver and celiac LN, when compared to other lymphoid organs, indicating that these are the initial sites of T cell activation. At the 3-week time point, there were fewer activated T cells in the liver and celiac LN in mice that received FTY720, while instead accumulating in the blood. Most likely, activated T cells were prevented from reentering the lymphoid organs from the circulation, where they were sequestered. We conclude that T cells are first activated by AAV8-Cyto-Ova in the liver and celiac LN after two weeks, where they subsequently egress into the circulation and re-enter lymphoid tissues, with many returning to the liver and celiac LN. FTY720 given at 2 weeks prevented the newly activated T cells from leaving the liver and celiac LN. These results strongly suggest that antigen presentation and CD4+ T cell activation occur first in the liver and celiac LN, beginning about 2 weeks after vector administration. Consistent with this conclusion, adoptively transferred Ova-specific CD4+ T cells proliferated first and to a much greater degree in the celiac LN of AAV8-Cyto-Ova transduced mice. Inactiviating Kupffer cells with gadolinium chloride significantly reduced antigen-specific proliferation, illustrating the requirement for professional resident liver antigen-presenting cells. Furthermore, we show that - in contrast to the AAV expression of secreted Ova - Treg are exclusively extrathymically induced after AAV8-Cyto-Ova vector administration. These Treg are found in high numbers in the blood after 2 weeks in mice given the FTY720 compound, suggesting that these peripherally induced Treg quickly enter the circulation. In conclusion, the liver and its draining celiac LN are key sites for antigen presentation and T cell activation in response to transgene expression directed by hepatic gene transfer. Presentation of antigen derived from a non-secreted transgene product induces FoxP3+ Treg that rapidly distribute through the circulation. Disclosures Herzog: Novo Nordisk: Research Funding; Spark Therapeutics: Patents & Royalties: Patent licenses.

Upregulation of TRAIL expression on human T lymphocytes by interferon b and glatiramer acetate

2005 ◽  
Vol 11 (6) ◽  
pp. 652-657 ◽  
Author(s):  
N Arbour ◽  
E Rastikerdar ◽  
E McCrea ◽  
Y Lapierre ◽  
J Dörr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Glatiramer Acetate ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Effects ◽  
Activated T Cells ◽  
Trail Expression

We measured the in vivo and in vitro effects of interferon (IFN)b and glatiramer acetate (GA) on the expression of the regulatory molecule, tumor necrosis factor related apoptosis inducing ligand (TRAIL), in patients with multiple sclerosis (MS). We confirmed the prior observation that TRAIL is enhanced on anti-CD3 activated T cells by the in vitro addition of IFNβ. T cells from IFNβ-treated patients stimulated with anti-CD3 only, had higher levels of TRAIL than untreated patients, suggesting that in vivo IFNβ exposure has an effect on TRAIL expression in association with T cell activation. In vitro IFNβ-induced TRAIL upregulation on anti-CD3 or phytohemagglutinin-activated T cells was comparable for IFNβ-treated and non-treated MS patients and controls, indicating that IFN receptors were neither saturated nor down-regulated by current IFNβ therapy. Although GAin vivo orin vitro did not induce TRAIL, the IFNβ-GA combination in vitro enhanced TRAIL expression to higher levels than IFNβ alone on CD4+ T cells obtained from MS patients, regardless of GA treatment status, and healthy donors, and on GA reactive T cell lines derived from GA-treated patients or controls. Whether any observed therapeutic effects of GA/IFNβ combination therapy will correlate with TRAIL expression and function remains to be determined.

scholarly journals The Ca2+-activated K+ channel KCa3.1 compartmentalizes in the immunological synapse of human T lymphocytes

2007 ◽  
Vol 292 (4) ◽  
pp. C1431-C1439 ◽  
Author(s):  
Stella A. Nicolaou ◽  
Lisa Neumeier ◽  
YouQing Peng ◽  
Daniel C. Devor ◽  
Laura Conforti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Cell Receptor ◽  
K Channel ◽  
Activated T Cells ◽  
Barr Virus

T cell receptor engagement results in the reorganization of intracellular and membrane proteins at the T cell-antigen presenting cell interface forming the immunological synapse (IS), an event required for Ca2+ influx. KCa3.1 channels modulate Ca2+ signaling in activated T cells by regulating the membrane potential. Nothing is known regarding KCa3.1 membrane distribution during T cell activation. Herein, we determined whether KCa3.1 translocates to the IS in human T cells using YFP-tagged KCa3.1 channels. These channels showed electrophysiological and pharmacological properties identical to wild-type channels. IS formation was induced by either anti-CD3/CD28 antibody-coated beads for fixed microscopy experiments or Epstein-Barr virus-infected B cells for fixed and live cell microscopy. In fixed microscopy experiments, T cells were also immunolabeled for F-actin or CD3ε, which served as IS formation markers. The distribution of KCa3.1 was determined with confocal and fluorescence microscopy. We found that, upon T cell activation, KCa3.1 channels localize with F-actin and CD3ε to the IS but remain evenly distributed on the cell membrane when no stimulus is provided. Detailed imaging experiments indicated that KCa3.1 channels are recruited in the IS shortly after antigen presentation and are maintained there for at least 15–30 min. Interestingly, pretreatment of activated T cells with the specific KCa3.1 blocker TRAM-34 blocked Ca2+ influx, but channel redistribution to the IS was not prevented. These results indicate that KCa3.1 channels are a part of the signaling complex that forms at the IS upon antigen presentation.

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