31 results on '"Ravens I"'
Search Results
2. Systems biology analysis reveals distinct molecular signatures associated with immune responsiveness to the BNT162b COVID-19 vaccine.
- Author
-
Odak I, Riemann L, Sandrock I, Cossmann A, Ramos GM, Hammerschmidt SI, Ritter C, Friedrichsen M, Hassan A, Dopfer-Jablonka A, Stankov MV, Weskamm LM, Addo MM, Ravens I, Willenzon S, Schimrock A, Ristenpart J, Janssen A, Barros-Martins J, Hansen G, Falk C, Behrens GMN, and Förster R
- Subjects
- Humans, Female, Cytokines genetics, Vaccination, Systems Biology methods, RNA, Messenger, Antibodies, Viral, COVID-19 Vaccines, COVID-19 prevention & control
- Abstract
Background: Human immune responses to COVID-19 vaccines display a large heterogeneity of induced immunity and the underlying immune mechanisms for this remain largely unknown., Methods: Using a systems biology approach, we longitudinally profiled a unique cohort of female high and low responders to the BNT162b vaccine, who were known from previous COVID-19 vaccinations to develop maximum and minimum immune responses to the vaccine. We utilized high dimensional flow cytometry, bulk and single cell mRNA sequencing and 48-plex serum cytokine analyses., Findings: We revealed early, transient immunological and molecular signatures that distinguished high from low responders and correlated with B and T cell responses measured 14 days later. High responders featured a distinct transcriptional activity of interferon-driven genes and genes connected to enhanced antigen presentation. This was accompanied by a robust cytokine response related to Th1 differentiation. Both transcriptome and serum cytokine signatures were confirmed in two independent confirmatory cohorts., Interpretation: Collectively, our data contribute to a better understanding of the immunogenicity of mRNA-based COVID-19 vaccines, which might lead to the optimization of vaccine designs for individuals with poor vaccine responses., Funding: German Center for Infection Research, German Center for Lung Research, German Research Foundation, Excellence Strategy EXC 2155 "RESIST" and European Regional Development Fund., Competing Interests: Declaration of interests G.H. reports grants from the German Federal Ministry of Education and Research, German Center for Lung Research, and German Research Foundation as well as personal fees from Sanofi GmbH, MedUpdate, and Abbvie. A.D-J served as an advisor or speaker from Novartis and Astra-Zeneca unrelated to this work. Funding parties had no role in study design, data collection, data analyses, interpretation, or writing of report. The other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
3. Humoral and cellular immune responses following BNT162b2 XBB.1.5 vaccination.
- Author
-
Stankov MV, Hoffmann M, Gutierrez Jauregui R, Cossmann A, Morillas Ramos G, Graalmann T, Winter EJ, Friedrichsen M, Ravens I, Ilievska T, Ristenpart J, Schimrock A, Willenzon S, Ahrenstorf G, Witte T, Förster R, Kempf A, Pöhlmann S, Hammerschmidt SI, Dopfer-Jablonka A, and Behrens GMN
- Subjects
- Humans, Antibodies, Viral, Vaccination, BNT162 Vaccine, Immunity, Cellular
- Abstract
Competing Interests: MH, AK, and SP did the contract research (testing of vaccinee sera for neutralising activity against SARS-CoV-2) for Valneva, unrelated to this work. GMNB served as an adviser for Moderna, unrelated to this work. SP served as an adviser for BioNTech, unrelated to this work. AD-J and TW served as an adviser for Pfizer, unrelated to this work. All other authors declare no competing interests. MVS, MH, and RGJ are co-first authors. AD-J and GMNB are co-senior authors.
- Published
- 2024
- Full Text
- View/download PDF
4. Omicron infection-associated T- and B-cell immunity in antigen-naive and triple-COVID-19-vaccinated individuals.
- Author
-
Barros-Martins J, Hammerschmidt SI, Morillas Ramos G, Cossmann A, Hetzel L, Odak I, Köhler M, Stankov MV, Ritter C, Friedrichsen M, Ravens I, Schimrock A, Ristenpart J, Janssen A, Willenzon S, Bernhardt G, Lichtinghagen R, Bošnjak B, Behrens GMN, and Förster R
- Subjects
- Humans, COVID-19 Vaccines, SARS-CoV-2, Antibodies, Neutralizing, Breakthrough Infections, COVID-19
- Abstract
Since early 2022, various Omicron variants have dominated the SARS-CoV-2 pandemic in most countries. All Omicron variants are B-cell immune escape variants, and antibodies induced by first-generation COVID-19 vaccines or by infection with earlier SARS-CoV-2 variants largely fail to protect individuals from Omicron infection. In the present study, we investigated the effect of Omicron infections in triple-vaccinated and in antigen-naive individuals. We show that Omicron breakthrough infections occurring 2-3.5 months after the third vaccination restore B-cell and T-cell immune responses to levels similar to or higher than those measured 14 days after the third vaccination, including the induction of Omicron-neutralizing antibodies. Antibody responses in breakthrough infection derived mostly from cross-reacting B cells, initially induced by vaccination, whereas Omicron infections in antigen-naive individuals primarily generated B cells binding to the Omicron but not the Wuhan spike protein. Although antigen-naive individuals mounted considerable T-cell responses after infection, B-cell responses were low, and neutralizing antibodies were frequently below the limit of detection. In summary, the detection of Omicron-associated B-cell responses in primed and in antigen-naive individuals supports the application of Omicron-adapted COVID-19 vaccines, but calls into question their suitability if they also contain/encode antigens of the original Wuhan virus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Barros-Martins, Hammerschmidt, Morillas Ramos, Cossmann, Hetzel, Odak, Köhler, Stankov, Ritter, Friedrichsen, Ravens, Schimrock, Ristenpart, Janssen, Willenzon, Bernhardt, Lichtinghagen, Bošnjak, Behrens and Förster.)
- Published
- 2023
- Full Text
- View/download PDF
5. Establishment and Functional Characterization of Murine Monoclonal Antibodies Recognizing Neuritin.
- Author
-
Papadogianni G, Ravens I, Hassan A, Flatley A, Feederle R, Bernhardt G, and Georgiev H
- Abstract
Neuritin represents a neurotrophic factor that is not only important in neuronal development and plasticity but also impacts endothelial angiogenesis, cell migration, tumor growth and the production of antibodies by B cells. We established monoclonal mouse anti-mouse neuritin antibodies by immunizing knock-out mice with two different neuritin-derived peptides. Because neuritin is well conserved between species, these new monoclonal antibodies recognize the neuritin of a wide variety of species, including human. Moreover, they not only recognize specifically surface-bound neuritin expressed by murine follicular regulatory T cells but also the block binding of recombinant neuritin to germinal center B cells. This suggests that these newly generated tools will be of great use in studying neuritin expression and function.
- Published
- 2023
- Full Text
- View/download PDF
6. BNT162b2-boosted immune responses six months after heterologous or homologous ChAdOx1nCoV-19/BNT162b2 vaccination against COVID-19.
- Author
-
Behrens GMN, Barros-Martins J, Cossmann A, Ramos GM, Stankov MV, Odak I, Dopfer-Jablonka A, Hetzel L, Köhler M, Patzer G, Binz C, Ritter C, Friedrichsen M, Schultze-Florey C, Ravens I, Willenzon S, Bubke A, Ristenpart J, Janssen A, Ssebyatika G, Krähling V, Bernhardt G, Hoffmann M, Pöhlmann S, Krey T, Bošnjak B, Hammerschmidt SI, and Förster R
- Subjects
- Antibodies, Neutralizing, Antibodies, Viral, Antibody Formation, BNT162 Vaccine, Humans, SARS-CoV-2, Vaccination, Vaccines, Synthetic, mRNA Vaccines, COVID-19 prevention & control
- Abstract
Heterologous prime/boost vaccination with a vector-based approach (ChAdOx-1nCov-19, ChAd) followed by an mRNA vaccine (e.g. BNT162b2, BNT) has been reported to be superior in inducing protective immunity compared to repeated application of the same vaccine. However, data comparing immunity decline after homologous and heterologous vaccination as well as effects of a third vaccine application after heterologous ChAd/BNT vaccination are lacking. Here we show longitudinal monitoring of ChAd/ChAd (n = 41) and ChAd/BNT (n = 88) vaccinated individuals and the impact of a third vaccination with BNT. The third vaccination greatly augments waning anti-spike IgG but results in only moderate increase in spike-specific CD4 + and CD8 + T cell numbers in both groups, compared to cell frequencies already present after the second vaccination in the ChAd/BNT group. More importantly, the third vaccination efficiently restores neutralizing antibody responses against the Alpha, Beta, Gamma, and Delta variants of the virus, but neutralizing activity against the B.1.1.529 (Omicron) variant remains severely impaired. In summary, inferior SARS-CoV-2 specific immune responses following homologous ChAd/ChAd vaccination can be compensated by heterologous BNT vaccination, which might influence the choice of vaccine type for subsequent vaccination boosts., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
7. Longitudinal Tracking of Immune Responses in COVID-19 Convalescents Reveals Absence of Neutralization Activity Against Omicron and Staggered Impairment to Other SARS-CoV-2 Variants of Concern.
- Author
-
Odak I, Schultze-Florey CR, Hammerschmidt SI, Ritter C, Willenzon S, Friedrichsen M, Ravens I, Sikora R, Bayir LM, Gutierrez Jauregui R, Bernhardt G, Stankov MV, Cossmann A, Hansen G, Krey T, Cornberg M, Koenecke C, Behrens GMN, Bošnjak B, and Förster R
- Subjects
- Antibodies, Neutralizing, Convalescence, Humans, Immunity, Humoral, Immunoglobulin G, Prospective Studies, Spike Glycoprotein, Coronavirus genetics, COVID-19, SARS-CoV-2
- Abstract
Evaluating long-term protection against SARS-CoV-2 variants of concern in convalescing individuals is of high clinical relevance. In this prospective study of a cohort of 46 SARS-CoV-2 patients infected with the Wuhan strain of SARS-CoV-2 we longitudinally analyzed changes in humoral and cellular immunity upon early and late convalescence. Antibody neutralization capacity was measured by surrogate virus neutralization test and cellular responses were investigated with 31-colour spectral flow cytometry. Spike-specific, isotype-switched B cells developed already during the disease phase, showed a memory phenotype and did not decrease in numbers even during late convalescence. Otherwise, no long-lasting perturbations of the immune compartment following COVID-19 clearance were observed. During convalescence anti-Spike (S1) IgG antibodies strongly decreased in all patients. We detected neutralizing antibodies against the Wuhan strain as well as the Alpha and Delta but not against the Beta, Gamma or Omicron variants for up to 7 months post COVID-19. Furthermore, correlation analysis revealed a strong association between sera anti-S1 IgG titers and their neutralization capacity against the Wuhan strain as well as Alpha and Delta. Overall, our data suggest that even 7 month after the clearance of COVID-19 many patients possess a protective layer of immunity, indicated by the persistence of Spike-specific memory B cells and by the presence of neutralizing antibodies against the Alpha and Delta variants. However, lack of neutralizing antibodies against the Beta, Gamma and Omicron variants even during the peak response is of major concern as this indicates viral evasion of the humoral immune response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Odak, Schultze-Florey, Hammerschmidt, Ritter, Willenzon, Friedrichsen, Ravens, Sikora, Bayir, Gutierrez Jauregui, Bernhardt, Stankov, Cossmann, Hansen, Krey, Cornberg, Koenecke, Behrens, Bošnjak and Förster.)
- Published
- 2022
- Full Text
- View/download PDF
8. The impact of stress on the transcriptomic signature of iNKT1 cells.
- Author
-
Papadogianni G, Ravens I, Hassan A, Dittrich-Breiholz O, Bernhardt G, and Georgiev H
- Abstract
Invariant natural killer T (iNKT) cells develop in thymus before emigrating and settling peripheral tissues and organs. In contrast to regular naïve T cells, most iNKT cells do not continuously recirculate but are rather sessile and can adopt phenotypically as well as functionally to their tissue environment. To explore this in more detail, we focused on the most widely distributed CD4
+ iNKT1 cells and compared the transcriptome of cells isolated from liver and spleen. Whereas there are only very few genuine differences in the transcriptomes of CD4+ iNKT1 cells of these two organs, the mode of cell isolation left clear marks in the transcriptomic signature. In contrast to liver cell isolated in the cold, cells prepared by enzymatic tissue digestion upregulated quickly a series of genes known to respond to stress. Therefore, to avoid erroneous conclusions, a comparison of expression profiles must take into consideration the history of cell preparation., Competing Interests: The authors declare no competing financial interests., (© 2021 The Authors.)- Published
- 2021
- Full Text
- View/download PDF
9. Neutralization of the SARS-CoV-2 Delta variant after heterologous and homologous BNT162b2 or ChAdOx1 nCoV-19 vaccination.
- Author
-
Hammerschmidt SI, Bosnjak B, Bernhardt G, Friedrichsen M, Ravens I, Dopfer-Jablonka A, Hoffmann M, Pöhlmann S, Behrens GMN, and Förster R
- Subjects
- Antibody Formation, BNT162 Vaccine, COVID-19 immunology, COVID-19 prevention & control, COVID-19 Vaccines immunology, ChAdOx1 nCoV-19, Female, Humans, Male, COVID-19 virology, COVID-19 Vaccines administration & dosage, SARS-CoV-2 physiology
- Published
- 2021
- Full Text
- View/download PDF
10. Immune responses against SARS-CoV-2 variants after heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination.
- Author
-
Barros-Martins J, Hammerschmidt SI, Cossmann A, Odak I, Stankov MV, Morillas Ramos G, Dopfer-Jablonka A, Heidemann A, Ritter C, Friedrichsen M, Schultze-Florey C, Ravens I, Willenzon S, Bubke A, Ristenpart J, Janssen A, Ssebyatika G, Bernhardt G, Münch J, Hoffmann M, Pöhlmann S, Krey T, Bošnjak B, Förster R, and Behrens GMN
- Subjects
- BNT162 Vaccine, CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, COVID-19 immunology, ChAdOx1 nCoV-19, Humans, Immunization, Secondary methods, Immunogenicity, Vaccine immunology, Spike Glycoprotein, Coronavirus immunology, Vaccination, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 Vaccines adverse effects, COVID-19 Vaccines immunology, SARS-CoV-2 immunology
- Abstract
Currently approved viral vector-based and mRNA-based vaccine approaches against coronavirus disease 2019 (COVID-19) consider only homologous prime-boost vaccination. After reports of thromboembolic events, several European governments recommended using AstraZeneca's ChAdOx1-nCov-19 (ChAd) only in individuals older than 60 years, leaving millions of already ChAd-primed individuals with the decision to receive either a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical School's COVID-19 Contact Study cohort of healthcare professionals to monitor ChAd-primed immune responses before and 3 weeks after booster with ChAd (n = 32) or BioNTech/Pfizer's BNT162b2 (n = 55). Although both vaccines boosted prime-induced immunity, BNT162b2 induced significantly higher frequencies of spike-specific CD4
+ and CD8+ T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and P.1 variants of concern of severe acute respiratory syndrome coronavirus 2., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
11. Low serum neutralizing anti-SARS-CoV-2 S antibody levels in mildly affected COVID-19 convalescent patients revealed by two different detection methods.
- Author
-
Bošnjak B, Stein SC, Willenzon S, Cordes AK, Puppe W, Bernhardt G, Ravens I, Ritter C, Schultze-Florey CR, Gödecke N, Martens J, Kleine-Weber H, Hoffmann M, Cossmann A, Yilmaz M, Pink I, Hoeper MM, Behrens GMN, Pöhlmann S, Blasczyk R, Schulz TF, and Förster R
- Subjects
- Adult, Aged, Angiotensin-Converting Enzyme 2 metabolism, COVID-19 blood, Cell Line, Convalescence, Female, Humans, Immunoglobulin A blood, Immunoglobulin G blood, Male, Middle Aged, Neutralization Tests methods, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 immunology, Spike Glycoprotein, Coronavirus immunology
- Abstract
Neutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells via surface-expressed angiotensin-converting enzyme 2 (ACE2). We used a surrogate virus neutralization test (sVNT) and SARS-CoV-2 S protein-pseudotyped vesicular stomatitis virus (VSV) vector-based neutralization assay (pVNT) to assess the degree to which serum antibodies from coronavirus disease 2019 (COVID-19) convalescent patients interfere with the binding of SARS-CoV-2 S to ACE2. Both tests revealed neutralizing anti-SARS-CoV-2 S antibodies in the sera of ~90% of mildly and 100% of severely affected COVID-19 convalescent patients. Importantly, sVNT and pVNT results correlated strongly with each other and to the levels of anti-SARS-CoV-2 S1 IgG and IgA antibodies. Moreover, levels of neutralizing antibodies correlated with the duration and severity of clinical symptoms but not with patient age. Compared to pVNT, sVNT is less sophisticated and does not require any biosafety labs. Since this assay is also much faster and cheaper, sVNT will not only be important for evaluating the prevalence of neutralizing antibodies in a population but also for identifying promising plasma donors for successful passive antibody therapy.
- Published
- 2021
- Full Text
- View/download PDF
12. Impact of Aging on the Phenotype of Invariant Natural Killer T Cells in Mouse Thymus.
- Author
-
Papadogianni G, Ravens I, Dittrich-Breiholz O, Bernhardt G, and Georgiev H
- Subjects
- Age Factors, Aging genetics, Aging metabolism, Animals, Cell Proliferation, Cells, Cultured, Cellular Senescence, Cytokines genetics, Cytokines metabolism, Female, Gene Expression Regulation, Immunosenescence, Interleukin-2 pharmacology, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells drug effects, Natural Killer T-Cells metabolism, Phenotype, Thymus Gland drug effects, Thymus Gland metabolism, Transcriptome, src-Family Kinases genetics, src-Family Kinases metabolism, Aging immunology, Natural Killer T-Cells immunology, Thymus Gland immunology
- Abstract
Invariant natural killer T (iNKT) cells represent a subclass of T cells possessing a restricted repertoire of T cell receptors enabling them to recognize lipid derived ligands. iNKT cells are continuously generated in thymus and differentiate into three main subpopulations: iNKT1, iNKT2, and iNKT17 cells. We investigated the transcriptomes of these subsets comparing cells isolated from young adult (6-10 weeks old) and aged BALB/c mice (25-30 weeks of age) in order to identify genes subject to an age-related regulation of expression. These time points were selected to take into consideration the consequences of thymic involution that radically alter the existing micro-milieu. Significant differences were detected in the expression of histone genes affecting all iNKT subsets. Also the proliferative capacity of iNKT cells decreased substantially upon aging. Several genes were identified as possible candidates causing significant age-dependent changes in iNKT cell generation and/or function such as genes coding for granzyme A, ZO-1, EZH2, SOX4, IGF1 receptor, FLT4, and CD25. Moreover, we provide evidence that IL2 differentially affects homeostasis of iNKT subsets with iNKT17 cells engaging a unique mechanism to respond to IL2 by initiating a slow rate of proliferation., (Copyright © 2020 Papadogianni, Ravens, Dittrich-Breiholz, Bernhardt and Georgiev.)
- Published
- 2020
- Full Text
- View/download PDF
13. IL-15 and CD155 expression regulate LAT expression in murine DNAM1 + NK cells, enhancing their effectors functions.
- Author
-
Luu TT, Wagner AK, Schmied L, Meinke S, Freund JE, Kambayashi T, Ravens I, Achour A, Bernhardt G, Chambers BJ, Höglund P, and Kadri N
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Antigens, Differentiation, T-Lymphocyte metabolism, Calcium Signaling, Cells, Cultured, Cytotoxicity, Immunologic, DNA-Binding Proteins genetics, Interleukin-15 genetics, Large Neutral Amino Acid-Transporter 1 genetics, Lymphocyte Activation, Lymphocyte Depletion, Mice, Mice, Inbred C57BL, Mice, Knockout, Nuclear Proteins genetics, Receptors, Virus genetics, Transcription Factors genetics, Transcriptional Activation, Adaptor Proteins, Signal Transducing metabolism, Interleukin-15 metabolism, Killer Cells, Natural immunology, Large Neutral Amino Acid-Transporter 1 metabolism, Receptors, Virus metabolism
- Abstract
NK cells are innate immune cells characterized by their ability to spontaneously lyse tumor and virally infected cells. We have recently demonstrated that IL-15-sufficient DC regulate NK cell effector functions in mice. Here, we established that among ITAM-proximal signaling molecules, the expression levels of the scaffold molecule Linker for Activation of T cells (LAT) and its transcription factor ELF-1 were reduced 4 days after in vivo depletion of DC. Addition of IL-15, a cytokine presented by DC to NK cells, regulates LAT expression in NK cells with a significant effect on the DNAM1
+ subset compared to DNAM1- cells. We also found that LAT expression is regulated via interaction of the DNAM1 receptor with its ligand CD155 in both immature and mature NK cells, independently of NK cell education. Finally, we found that LAT expression within DNAM1+ NK cells might be responsible for enhanced calcium mobilization following the triggering of activating receptors on NK cells. Altogether, we found that LAT expression is tightly regulated in DNAM1+ NK cells, via interaction(s) with DC, which express CD155 and IL-15, resulting in rapid activation of the DNAM1+ subset during activating receptor triggering., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2020
- Full Text
- View/download PDF
14. Publisher Correction: Human γδ T cells are quickly reconstituted after stem-cell transplantation and show adaptive clonal expansion in response to viral infection.
- Author
-
Ravens S, Schultze-Florey C, Raha S, Sandrock I, Drenker M, Oberdörfer L, Reinhardt A, Ravens I, Beck M, Geffers R, von Kaisenberg C, Heuser M, Thol F, Ganser A, Förster R, Koenecke C, and Prinz I
- Abstract
In the version of this article initially published, a source of funding (Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R12/29 to C.K. and I.P.)) was not included in the Acknowledgments section. The correct statement is as follows: "Supported by Deutsche Forschungsgemeinschaft, (SFB900/B8 to C.K. and I.P.; and PR727/4-1 to I.P.), Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R12/29 to C.K. and I.P.) and the German Federal Ministry of Education and Research (01EO1302 to C.S.-F., C.K. and I.P.)." The error has been corrected in the HTML and PDF versions of the article.
- Published
- 2018
- Full Text
- View/download PDF
15. Blocking the ART2.2/P2X7-system is essential to avoid a detrimental bias in functional CD4 T cell studies.
- Author
-
Georgiev H, Ravens I, Papadogianni G, Malissen B, Förster R, and Bernhardt G
- Subjects
- 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine analogs & derivatives, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine pharmacology, Adenosine Triphosphate metabolism, Animals, Apoptosis, Cell Survival, Cells, Cultured, Mice, Mice, Inbred C57BL, Mice, Transgenic, NAD metabolism, Receptors, Purinergic P2X7 genetics, ADP Ribose Transferases metabolism, CD4-Positive T-Lymphocytes immunology, Ion Transport drug effects, Receptors, Purinergic P2X7 metabolism, T-Lymphocyte Subsets immunology
- Abstract
Murine T cell subsets differ in their expression level of P2X7. Depending on several parameters like extracellular NAD
+ , P2X7 can be ADP-ribosylated rapidly by adjacent ARTC2.2 resulting in susceptibilities to apoptosis to a varying extent. This detrimental effect can be prevented when drugs like KN-62 are present during cell preparations., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2018
- Full Text
- View/download PDF
16. Coming of Age: CD96 Emerges as Modulator of Immune Responses.
- Author
-
Georgiev H, Ravens I, Papadogianni G, and Bernhardt G
- Subjects
- Animals, Antigen Presentation immunology, Antigens, CD chemistry, Antigens, CD genetics, Antigens, Differentiation, T-Lymphocyte immunology, Antigens, Differentiation, T-Lymphocyte metabolism, Biomarkers, Tumor, Gene Expression Regulation, Humans, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Molecular Targeted Therapy, Neoplasms diagnosis, Neoplasms drug therapy, Neoplasms etiology, Neoplasms metabolism, Signal Transduction, Structure-Activity Relationship, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Antigens, CD immunology, Antigens, CD metabolism, Immunity, Immunomodulation
- Abstract
CD96 represents a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily. CD96 is expressed mainly by cells of hematopoietic origin, in particular on T and NK cells. Upon interaction with CD155 present on target cells, CD96 was found to inhibit mouse NK cells, and absence of this interaction either by blocking with antibody or knockout of CD96 showed profound beneficial effects in containment of tumors and metastatic spread in murine model systems. However, our knowledge regarding CD96 functions remains fragmentary. In this review, we will discuss structural features of CD96 and their putative impact on function as well as some unresolved issues such as a potential activation that may be conferred by human but not mouse CD96. This is of importance for translation into human cancer therapy. We will also address CD96 activities in the context of the immune regulatory network that consists of CD155, CD96, CD226, and TIGIT.
- Published
- 2018
- Full Text
- View/download PDF
17. Shared and Unique Features Distinguishing Follicular T Helper and Regulatory Cells of Peripheral Lymph Node and Peyer's Patches.
- Author
-
Georgiev H, Ravens I, Papadogianni G, Halle S, Malissen B, Loots GG, Förster R, and Bernhardt G
- Subjects
- Animals, Biomarkers, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, Cytokines metabolism, Gene Expression Profiling, Immunophenotyping, Lymphocyte Activation immunology, Mice, Phenotype, Transcriptome, Lymph Nodes immunology, Peyer's Patches immunology, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism
- Abstract
Follicular helper (TFH) and regulatory (TFR) cells are critical players in managing germinal center (GC) reactions that accomplish effective humoral immune responses. Transcriptome analyses were done comparing gene regulation of TFH and TFR cells isolated from Peyer's Patches (PP) and immunized peripheral lymph nodes (pLNs) revealing many regulatory patterns common to all follicular cells. However, in contrast to TFH cells, the upregulation or downregulation of many genes was attenuated substantially in pLN TFR cells when compared to those of PP. Additionally, PP but not pLN TFR cells were largely unresponsive to IL2 and expressed Il4 as well as Il21 . Together with fundamental differences in gene expression that were found between cells of both compartments this emphasizes specific adaptations of follicular T cell functions to their micro-milieu. Moreover, although GL7 expression distinguishes matured follicular T cells, GL7
+ as well as GL7- cells are present in the GC.- Published
- 2018
- Full Text
- View/download PDF
18. Human γδ T cells are quickly reconstituted after stem-cell transplantation and show adaptive clonal expansion in response to viral infection.
- Author
-
Ravens S, Schultze-Florey C, Raha S, Sandrock I, Drenker M, Oberdörfer L, Reinhardt A, Ravens I, Beck M, Geffers R, von Kaisenberg C, Heuser M, Thol F, Ganser A, Förster R, Koenecke C, and Prinz I
- Subjects
- Cytomegalovirus Infections genetics, Cytomegalovirus Infections virology, Gene Rearrangement, T-Lymphocyte, Graft Survival, Humans, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Transplantation, Homologous, Clonal Evolution genetics, Clonal Evolution immunology, Cytomegalovirus Infections immunology, Hematopoietic Stem Cell Transplantation, Receptors, Antigen, T-Cell, gamma-delta genetics, Receptors, Antigen, T-Cell, gamma-delta metabolism, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
- Abstract
To investigate how the human γδ T cell pool is shaped during ontogeny and how it is regenerated after transplantation of hematopoietic stem cells (HSCs), we applied an RNA-based next-generation sequencing approach to monitor the dynamics of the repertoires of γδ T cell antigen receptors (TCRs) before and after transplantation in a prospective cohort study. We found that repertoires of rearranged genes encoding γδ TCRs (TRG and TRD) in the peripheral blood of healthy adults were stable over time. Although a large fraction of human TRG repertoires consisted of public sequences, the TRD repertoires were private. In patients undergoing HSC transplantation, γδ T cells were quickly reconstituted; however, they had profoundly altered TCR repertoires. Notably, the clonal proliferation of individual virus-reactive γδ TCR sequences in patients with reactivation of cytomegalovirus revealed strong evidence for adaptive anti-viral γδ T cell immune responses.
- Published
- 2017
- Full Text
- View/download PDF
19. Distinct gene expression patterns correlate with developmental and functional traits of iNKT subsets.
- Author
-
Georgiev H, Ravens I, Benarafa C, Förster R, and Bernhardt G
- Subjects
- Animals, Biomarkers metabolism, Cell Movement, Cytokines metabolism, Female, Lung cytology, Mice, Inbred BALB C, Mice, Inbred C57BL, Natural Killer T-Cells cytology, Phenotype, Receptors, Antigen, T-Cell metabolism, Receptors, Chemokine metabolism, Serpins deficiency, Serpins metabolism, Signal Transduction, Thymus Gland cytology, Transcriptome genetics, Gene Expression Profiling, Gene Expression Regulation, Natural Killer T-Cells metabolism, T-Lymphocyte Subsets metabolism
- Abstract
Invariant natural killer T (iNKT) cells comprise a subpopulation of innate lymphocytes developing in thymus. A new model proposes subdividing murine iNKT cells into iNKT1, 2 and 17 cells. Here, we use transcriptome analyses of iNKT1, 2 and 17 subsets isolated from BALB/c and C57BL/6 thymi to identify candidate genes that may affect iNKT cell development, migration or function. We show that Fcɛr1γ is involved in generation of iNKT1 cells and that SerpinB1 modulates frequency of iNKT17 cells. Moreover, a considerable proportion of iNKT17 cells express IL-4 and IL-17 simultaneously. The results presented not only validate the usefulness of the iNKT1/2/17-concept but also provide new insights into iNKT cell biology.
- Published
- 2016
- Full Text
- View/download PDF
20. Sensitivity of dendritic cells to NK-mediated lysis depends on the inflammatory environment and is modulated by CD54/CD226-driven interactions.
- Author
-
Smith LE, Olszewski MA, Georgoudaki AM, Wagner AK, Hägglöf T, Karlsson MC, Dominguez-Villar M, Garcia-Cozar F, Mueller S, Ravens I, Bernhardt G, and Chambers BJ
- Subjects
- Animals, Cells, Cultured, Dendritic Cells transplantation, Genes, RAG-1, Graft Rejection immunology, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Inflammation, Interleukin-18 pharmacology, Membrane Proteins pharmacology, Mice, Mice, Knockout, Programmed Cell Death 1 Receptor deficiency, Receptors, Virus deficiency, Recombinant Proteins pharmacology, Spleen immunology, Antigens, Differentiation, T-Lymphocyte immunology, Cytotoxicity, Immunologic immunology, Dendritic Cells immunology, Intercellular Adhesion Molecule-1 immunology, Killer Cells, Natural immunology
- Abstract
Previous studies have suggested that NK cells may limit T cell responses by their ability to eradicate dendritic cells, as demonstrated by NK cell-mediated killing of dendritic cells generated from mouse bone marrow cells or human monocytes with GM-CSF. In the present study, we demonstrated that conventional dendritic cells, generated in vitro with Flt3 ligand or from spleens, were resistant to NK cell-mediated lysis. However, upon stimulation with GM-CSF, NK cells could mediate lysis of these dendritic cells. GM-CSF-stimulated Flt3 ligand dendritic cells or splenic dendritic cells increased surface expression of costimulatory molecules and known NK cell ligands. Likewise, NK cells could target dendritic cells in vivo, which could be inhibited, in part, by anti-GM-CSF antibodies. The blocking of CD54 or CD226 inhibited NK cell-mediated cytotoxicity of the GM-CSF-stimulated Flt3 ligand conventional dendritic cells. Furthermore, the CD226
+ NKG2A- subset of NK cells was selectively better at targeting GM-CSF-stimulated Flt3 ligand conventional dendritic cells. However, CD155, a known ligand for CD226, could also act as an inhibitor of NK cell-mediated lysis, as dendritic cells lacking CD155 were more sensitive to NK cell-mediated lysis than wild-type dendritic cells. We hypothesize that by only permitting a subset of NK cells to target activated dendritic cells during inflammation, this would allow the immune system to balance between dendritic cells able to drive adaptive immune responses and dendritic cells targeted for elimination by NK cells to hinder, e.g., spread of infection., (© Society for Leukocyte Biology.)- Published
- 2016
- Full Text
- View/download PDF
21. CD155/CD226-interaction impacts on the generation of innate CD8(+) thymocytes by regulating iNKT-cell differentiation.
- Author
-
Georgiev H, Ravens I, Shibuya A, Förster R, and Bernhardt G
- Subjects
- Animals, Antigens, Differentiation, T-Lymphocyte immunology, Cell Differentiation immunology, Cell Movement immunology, Female, Immunologic Memory immunology, Interleukin-4 biosynthesis, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Natural Killer T-Cells cytology, Receptors, Virus immunology, Thymus Gland immunology, Antigens, Differentiation, T-Lymphocyte genetics, CD8-Positive T-Lymphocytes immunology, Natural Killer T-Cells immunology, Receptors, Virus genetics, Thymus Gland cytology
- Abstract
The cell surface receptor CD155 influences a variety of immune processes by binding to its ligands CD226, CD96, or TIGIT. Here, we report that the interaction of CD155 with CD226 in the thymus of BALB/c mice has a dual function. It directly influences the dwell time of memory-like CD8(+) T cells, while it is indirectly involved in generating these cells. It was shown earlier that a massive emergence of memory-like CD8 T cells in thymus crucially depends on abundant IL-4, secreted in steady state by iNKT2 (where iNKT is invariant NKT) cells, a subclass of iNKT cells. Here, we show that absence of either CD155 or CD226 in BALB/c mice causes a profound shift in the iNKT subtype composition in thymus, expanding the frequency and numbers of iNKT1 cells at the expense of iNKT2 cells, as well as iNKT17 cells. This shift results in a drop of available IL-4 and creates a scenario similar to that observed in C57BL/6 mice, where iNKT1 cells predominate and iNKT2 cells are much less frequent when compared with BALB/c mice. Yet also in C57BL/6 mice, lack of CD155 or CD226 provokes a further decline in iNKT2 cells, suggesting that the observed effects are not restricted to a particular inbred strain., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
- Full Text
- View/download PDF
22. The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation.
- Author
-
Kraus AK, Chen J, Edenhofer I, Ravens I, Gaspert A, Cippà PE, Mueller S, Wuthrich RP, Segerer S, Bernhardt G, and Fehr T
- Subjects
- Allografts, Animals, Antigens, Differentiation, T-Lymphocyte genetics, Cytotoxicity, Immunologic, Epithelial Cells metabolism, Gene Expression, Graft Rejection genetics, Graft Rejection immunology, Interleukin-2 Receptor beta Subunit genetics, Interleukin-2 Receptor beta Subunit metabolism, Kidney Tubules cytology, Kidney Tubules metabolism, Ligands, Lymphocyte Activation genetics, Mice, Mice, Knockout, Models, Animal, Receptors, Virus genetics, Receptors, Virus metabolism, Signal Transduction, Skin Transplantation, Antigens, Differentiation, T-Lymphocyte metabolism, Kidney Transplantation, Lymphocyte Activation immunology, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
DNAX accessory protein-1 (DNAM-1, CD226) is a co-stimulatory and adhesion molecule expressed mainly by natural killer cells and T cells. DNAM-1 and its two ligands CD112 and CD155 are important in graft-versus-host disease, but their role in solid organ transplantation is largely unknown. We investigated the relevance of this pathway in a mouse kidney transplantation model. CD112 and CD155 are constitutively expressed on renal tubular cells and strongly upregulated in acutely rejected renal allografts. In vitro DNAM-1 blockade during allogeneic priming reduced the allospecific T cell response but not the allospecific cytotoxicity against renal tubular epithelial cells. Accordingly, absence of DNAM-1 in recipient mice or absence of CD112 or CD155 in the kidney allograft did not significantly influence renal function and severity of rejection after transplantation, but led to a higher incidence of infarcts in CD112 and CD155 deficient kidney allografts. Thus, DNAM-1 blockade is not effective in preventing transplant rejection. Despite of being highly expressed, CD112 and CD155 do not appear to play a major immunogenic role in kidney transplantation. Considering the high incidence of renal infarcts in CD112 and CD155 deficient grafts, blocking these molecules might be detrimental.
- Published
- 2016
- Full Text
- View/download PDF
23. CD226 interaction with CD155 impacts on retention and negative selection of CD8 positive thymocytes as well as T cell differentiation to follicular helper cells in Peyer's Patches.
- Author
-
Danisch S, Qiu Q, Seth S, Ravens I, Dorsch M, Shibuya A, Shibuya K, Förster R, and Bernhardt G
- Subjects
- Animals, Antigens, Differentiation, T-Lymphocyte genetics, Cell Differentiation, Cell Movement immunology, Cells, Cultured, Clonal Selection, Antigen-Mediated, Mice, Mice, Inbred BALB C, Mice, Knockout, Protein Binding immunology, Thymocytes immunology, Thymus Gland immunology, Antigens, Differentiation, T-Lymphocyte metabolism, CD8-Positive T-Lymphocytes immunology, Peyer's Patches immunology, Receptors, Virus metabolism, T-Lymphocyte Subsets immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
The immunoglobulin-like glycoprotein CD226 represents a receptor activating cytotoxic T and NK cells taking part in tumour surveillance. In addition, CD226 is involved in the differentiation of naïve CD4(+) T cells into effector cells. CD155 that is widely over-expressed on tumour cells, was identified as a counter-receptor of CD226 rendering many cancer cells sensitive to NK driven elimination. However, CD155 was also assigned a role in the establishment of follicular helper T cells in the small intestine and the final maturation of CD8 positive thymocytes. Here we show that mice lacking CD226 are distinguished by virtually identical phenotypes as already reported for CD155 deficient mice: a paucity of follicular helper T cells in Peyer's Patches and of terminally matured CD8 T cells in thymus. Moreover, like CD155, CD226 is involved in negative selection of CD8 thymocytes. These observations establish a firm link between the functions of CD155 and CD226 in several T cell differentiation steps., (Copyright © 2012 Elsevier GmbH. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
24. Intranodal interaction with dendritic cells dynamically regulates surface expression of the co-stimulatory receptor CD226 protein on murine T cells.
- Author
-
Seth S, Qiu Q, Danisch S, Maier MK, Braun A, Ravens I, Czeloth N, Hyde R, Dittrich-Breiholz O, Förster R, and Bernhardt G
- Subjects
- Adoptive Transfer, Animals, Antibodies, Neutralizing pharmacology, Antigens, Differentiation, T-Lymphocyte biosynthesis, Antigens, Differentiation, T-Lymphocyte genetics, Cell Communication drug effects, Cell Communication genetics, Dendritic Cells cytology, Dendritic Cells metabolism, Lymph Nodes cytology, Lymph Nodes metabolism, Mice, Mice, Inbred BALB C, Mice, Knockout, Receptors, CCR7 genetics, Receptors, CCR7 immunology, Receptors, CCR7 metabolism, Receptors, Virus antagonists & inhibitors, Receptors, Virus genetics, Receptors, Virus immunology, Receptors, Virus metabolism, T-Lymphocytes cytology, T-Lymphocytes metabolism, Up-Regulation drug effects, Up-Regulation genetics, Antigens, Differentiation, T-Lymphocyte immunology, Cell Communication immunology, Dendritic Cells immunology, Lymph Nodes immunology, T-Lymphocytes immunology, Up-Regulation immunology
- Abstract
Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system. Depending on their maturation status, they prime T cells to induce adaptive immunity or tolerance. DCs express CD155, an immunoglobulin-like receptor binding CD226 present on T and natural killer (NK) cells. CD226 represents an important co-stimulator during T cell priming but also serves as an activating receptor on cytotoxic T and NK cells. Here, we report that cells of the T and NK cell lineage of CD155(-/-) mice express markedly elevated protein levels of CD226 compared with wild type (WT). On heterozygous CD155(+/-) T cells, CD226 up-regulation is half-maximal, implying an inverse gene-dosis effect. Moreover, CD226 up-regulation is independent of antigen-driven activation because it occurs already in thymocytes and naïve peripheral T cells. In vivo, neutralizing anti-CD155 antibody elicits up-regulation of CD226 on T cells demonstrating, that the observed modulation can be triggered by interrupting CD155-CD226 contacts. Adoptive transfers of WT or CD155(-/-) T cells into CD155(-/-) or WT recipients, respectively, revealed that CD226 modulation is accomplished in trans. Analysis of bone marrow chimeras showed that regulators in trans are of hematopoietic origin. We demonstrate that DCs are capable of manipulating CD226 levels on T cells in vivo but not in vitro, suggesting that the process of T cells actively scanning antigen-presenting DCs inside secondary lymphoid organs is required for CD226 modulation. Hence, a CD226 level divergent from WT may be exploited as a sensor to detect abnormal DC/T-cell cross-talk as illustrated for T cells in mice lacking CCR7.
- Published
- 2011
- Full Text
- View/download PDF
25. Absence of CD155 aggravates acute graft-versus-host disease.
- Author
-
Seth S, Ravens I, Lee CW, Glage S, Bleich A, Förster R, Bernhardt G, and Koenecke C
- Subjects
- Acute Disease, Animals, Humans, Mice, Mice, Knockout, T-Lymphocytes immunology, Graft vs Host Disease immunology, Receptors, Virus immunology
- Published
- 2011
- Full Text
- View/download PDF
26. CD155 is involved in negative selection and is required to retain terminally maturing CD8 T cells in thymus.
- Author
-
Qiu Q, Ravens I, Seth S, Rathinasamy A, Maier MK, Davalos-Misslitz A, Forster R, and Bernhardt G
- Subjects
- Aging genetics, Aging immunology, Animals, Apoptosis genetics, Apoptosis immunology, CD8-Positive T-Lymphocytes metabolism, Cell Differentiation genetics, Cell Movement genetics, Cellular Senescence genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Receptors, Virus deficiency, Receptors, Virus genetics, Thymus Gland metabolism, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Cell Movement immunology, Cellular Senescence immunology, Receptors, Virus physiology, Thymus Gland cytology, Thymus Gland immunology
- Abstract
During their final maturation in the medulla, semimature single-positive (SP) thymocytes downregulate activation markers and subsequently exit into the periphery. Although semimature CD4(+) SP cells are sensitive to negative selection, the timing of when negative selection occurs in the CD8 lineage remains elusive. We show that the abundance of terminally matured CD8(+) SP cells in adult thymus is modulated by the genetic background. Moreover, in BALB/c mice, the frequency of terminally matured CD8(+) SP cells, but not that of CD4(+) SP cells present in thymus, varies depending on age. In mice lacking expression of the adhesion receptor CD155, a selective deficiency of mature CD8(+) SP thymocytes was observed, emerging first in adolescent animals at the age when these cells start to accumulate in wild-type thymus. Evidence is provided that the mature cells emigrate prematurely when CD155 is absent, cutting short their retention time in the medulla. Moreover, in nonmanipulated wild-type mice, semimature CD8(+) SP thymocytes are subjected to negative selection, as reflected by the diverging TCR repertoires present on semimature and mature CD8(+) T cells. In CD155-deficient animals, a shift was found in the TCR repertoire displayed by the pool of CD8(+) SP cells, demonstrating that CD155 is involved in negative selection.
- Published
- 2010
- Full Text
- View/download PDF
27. Abundance of follicular helper T cells in Peyer's patches is modulated by CD155.
- Author
-
Seth S, Ravens I, Kremmer E, Maier MK, Hadis U, Hardtke S, Förster R, and Bernhardt G
- Subjects
- Animals, Antigens, Differentiation, T-Lymphocyte immunology, Cell Differentiation immunology, Cell Separation, Female, Flow Cytometry, Germinal Center cytology, Germinal Center immunology, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Peyer's Patches cytology, Receptors, Immunologic immunology, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Helper-Inducer cytology, Immunomodulation immunology, Lymphocyte Activation immunology, Peyer's Patches immunology, Receptors, Virus immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
The secondary humoral immune response is characterized by plasma B cells secreting isotype-switched and affinity-matured antibodies. The efficient generation of plasma B cells in the GC depends on the presence of follicular helper T (T(FH)) cells, a cell type thought to arise from naive CD4-positive T cells by a hitherto unresolved differentiation pathway. Mice deficient for CD155, an adhesion receptor of the immunoglobulin superfamily, are impaired to mount a secondary humoral immune response upon oral administration of antigen, while the primary IgM response is unaffected. Here, we show that mice lacking CD155 harbor significantly reduced numbers of T(FH) cells in their Peyer's patches. This was paralleled by a decreased frequency of T(FH) cells in the GC. Moreover, the CD155 ligand CD226, which is involved in T-cell activation, is down-regulated during T(FH) cell differentiation, resulting in a complete absence of CD226 on those T(FH) cells residing in the GC. Concurrently, the expression of TIGIT/WUCAM, a newly discovered CD155 ligand, is induced in T(FH) cells. Thus, these cells replace an activating by a putative inhibitory CD155-binding partner during their differentiation.
- Published
- 2009
- Full Text
- View/download PDF
28. Heterogeneous expression of the adhesion receptor CD226 on murine NK and T cells and its function in NK-mediated killing of immature dendritic cells.
- Author
-
Seth S, Georgoudaki AM, Chambers BJ, Qiu Q, Kremmer E, Maier MK, Czeloth N, Ravens I, Foerster R, and Bernhardt G
- Subjects
- Animals, Antigens, Differentiation, T-Lymphocyte analysis, Antigens, Differentiation, T-Lymphocyte metabolism, Binding Sites, Cytotoxicity, Immunologic, Gene Expression Regulation immunology, Mice, Protein Binding immunology, Receptors, Virus metabolism, Antigens, Differentiation, T-Lymphocyte immunology, Dendritic Cells cytology, Killer Cells, Natural immunology, Receptors, Virus immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
The adhesion receptor CD226 (DNAM-1) is a member of the Ig superfamily possessing two extracellular V-like domains. In humans, CD226 was shown to be expressed by NK as well as T cells. During T cell priming, CD226-mediated costimulatory signals may skew the subsequent differentiation into the Th1 pathway. In addition, CD226 expressed on NK and cytotoxic T cells is engaged by its counter-receptor CD155, present on target cells, thereby triggering their elimination. We established mAb specifically recognizing mCD226, demonstrating that CD226 is expressed by precursor and mature but not developing T cells. In contrast, NK cells are distinguished by a rather heterogeneous CD226 expression profile. In addition, expression of CD226 appears coupled to that of other NK cell receptors, as high expression of CD226 was found to correlate with decreased proportions of Ly49D and H positive NK cells. Upon injection into mice, the anti-CD226 antibodies caused selective depletion of CD8(+) T cells. Moreover, these antibodies as well as a naturally occurring CD226 splice variant lacking the outermost V-like domain were instrumental in determining that CD226 adheres to CD155 via its first domain. In addition, antibodies were identified as capable of blocking the CD226/CD155 interaction and to prevent NK-driven killing of immature DC. CD226 is thus the first mNK receptor identified to be essential for the elimination of this particular cell type.
- Published
- 2009
- Full Text
- View/download PDF
29. CD96 interaction with CD155 via its first Ig-like domain is modulated by alternative splicing or mutations in distal Ig-like domains.
- Author
-
Meyer D, Seth S, Albrecht J, Maier MK, du Pasquier L, Ravens I, Dreyer L, Burger R, Gramatzki M, Schwinzer R, Kremmer E, Foerster R, and Bernhardt G
- Subjects
- Amino Acid Sequence, Animals, Antigens, CD chemistry, Antigens, CD genetics, Cell Line, Humans, Immunoglobulins genetics, Ligands, Mice, Molecular Sequence Data, Mutation genetics, Protein Binding, Protein Folding, Receptors, Virus genetics, Sequence Alignment, Alternative Splicing genetics, Antigens, CD immunology, Antigens, CD metabolism, Immunoglobulins immunology, Immunoglobulins metabolism, Receptors, Virus immunology, Receptors, Virus metabolism
- Abstract
The adhesion receptor CD96 (TACTILE) is a transmembrane glycoprotein possessing three extracellular immunoglobulin-like domains. Among peripheral blood cells, CD96 is expressed on T cells as well as NK cells and a subpopulation of B cells. A possible function of this receptor in NK cell-mediated killing activities was suggested recently. Moreover, CD96 was described as a tumor marker for T-cell acute lymphoblastic leukemia and acute myeloid leukemia. CD96 binds to CD155 (poliovirus receptor) and nectin-1, an adhesion receptor related to CD155. Here we report that human but not mouse CD96 is expressed in two splice variants possessing either an I-like (variant 1) or V-like (variant 2) second domain. With the notable exception of an AML tumor sample, variant 2 predominates in all the CD96-expressing cell types and tissues examined. Using chimeric human/murine CD96 receptors, we show that the interaction with its ligands is mediated via the outermost V-like domain. In contrast to mouse, however, the binding of human CD96 to CD155 is sensitive to the characteristics of the two downstream domains. This is illustrated by a significantly weaker CD96/CD155 interaction mediated by variant 1 when compared with variant 2. Moreover, recent evidence suggested that mutations in human CD96 correlate with the occurrence of a rare form of trigonocephaly. One such mutation causing a single amino acid exchange in the third domain of human CD96 decreased the capacity of both variants to bind to CD155 considerably, suggesting that a CD96-driven adhesion to CD155 may be crucial in developmental processes.
- Published
- 2009
- Full Text
- View/download PDF
30. The adhesion receptor CD155 determines the magnitude of humoral immune responses against orally ingested antigens.
- Author
-
Maier MK, Seth S, Czeloth N, Qiu Q, Ravens I, Kremmer E, Ebel M, Müller W, Pabst O, Förster R, and Bernhardt G
- Subjects
- Administration, Oral, Animals, Antigens immunology, B-Lymphocytes immunology, B-Lymphocytes metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Expression, Gene Expression Profiling, Immunohistochemistry, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Membrane Proteins deficiency, Mice, Mice, Knockout, Monocytes immunology, Monocytes metabolism, Plasma Cells immunology, Plasma Cells metabolism, Rats, Receptors, Virus deficiency, T-Lymphocytes immunology, T-Lymphocytes metabolism, Antibodies, Monoclonal immunology, Antibody Formation, Antigens administration & dosage, Membrane Proteins immunology, Receptors, Virus immunology
- Abstract
CD155, originally known as the cellular receptor for poliovirus, is the founding member of a subfamily of immunoglobulin-like adhesion receptors. Apart from its function in establishing adherens junctions between contacting epithelial cells, the engagement of CD155 with two recently identified ligands, CD226 and CD96, mediates immunologically relevant processes such as NK cell-driven killing of tumor cells in humans. Here we report on the generation and immunological analysis of mice constitutively deficient of CD155. Moreover, the expression profile of CD155 on hematopoietic cells has been determined using newly established antibodies. CD155-deficient mice develop normally without displaying an overt phenotype. However, the animals are distinguished by distinct deficits in the development of a regular humoral immune response. Whereas systemic challenges revealed no differences, orally administered antigen evoked less efficient IgG and IgA antibody responses despite of normal IgM titers when compared to wild-type mice. Therefore, CD155 may assist in an efficient humoral immune response generated within the intestinal immune system.
- Published
- 2007
- Full Text
- View/download PDF
31. Characterization and identification of Tage4 as the murine orthologue of human poliovirus receptor/CD155.
- Author
-
Ravens I, Seth S, Förster R, and Bernhardt G
- Subjects
- Amino Acid Sequence, Animals, Antigens, Neoplasm genetics, Cell Adhesion physiology, Cell Adhesion Molecules genetics, Cell Line, Fibroblasts chemistry, Fibroblasts metabolism, Humans, Kidney chemistry, Kidney metabolism, Lung chemistry, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Neoplasm Proteins genetics, Organ Specificity, Protein Binding, Receptors, Virus genetics, Recombinant Proteins, Sequence Homology, Amino Acid, Species Specificity, Tissue Distribution, Antigens, Neoplasm chemistry, Antigens, Neoplasm metabolism, Cell Adhesion Molecules chemistry, Cell Adhesion Molecules metabolism, Lung metabolism, Membrane Proteins, Neoplasm Proteins chemistry, Neoplasm Proteins metabolism, Receptors, Virus chemistry, Receptors, Virus metabolism, Vitronectin chemistry
- Abstract
CD155 is a member of the immunoglobulin superfamily also known as the human receptor for poliovirus (PVR). Transmembrane glycoproteins related to CD155, the nectins, are well-characterized cell adhesion receptors displaying a high degree of sequence conservation across species. In contrast, CD155 belongs to the category of rapidly evolving genes wherefore a mouse CD155 gene distinguished by an affirmative extent of amino acid conservation as observed for nectins is absent. Consequently, the existing genetic evidence by itself is an inferior indicator to consider whether Tage4, a mouse orphan receptor, represents the murine orthologue of CD155. In the present study Tage4 cDNA was cloned from mouse lung and further characterized genetically. CD155 and Tage4 possess an identical genomic organization and reside in syntenic chromosomal regions. The Tage4 expression pattern was explored applying a newly generated antibody. Both receptors, CD155 in human and Tage4 in mouse, are expressed by intestinal epithelia as well as by follicle associated epithelium and follicular dendritic cells inside Peyer's patches of the gut associated lymphoid tissue. Furthermore, Tage4 lacks self-adhesion capacity but binds to vitronectin, two known features of CD155. These data indicate that Tage4 represents the functional orthologue of CD155 in mouse. Therefore, we suggest to rename Tage4 into rodent CD155.
- Published
- 2003
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.