scholarly journals Induction of a Polarized Th1 Response by Insertion of Multiple Copies of a Viral T-Cell Epitope into Adenylate Cyclase of Bordetella pertussis

2000 ◽  
Vol 68 (7) ◽  
pp. 3867-3872 ◽  
Author(s):  
Gilles Dadaglio ◽  
Zhora Moukrim ◽  
Richard Lo-Man ◽  
Valeria Sheshko ◽  
Peter Sebo ◽  
...  
Keyword(s):  
T Cell ◽  
Adenylate Cyclase ◽  
Bordetella Pertussis ◽  
Catalytic Domain ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Th1 Response ◽  
Presentation Pathway ◽  
Ctl Responses

ABSTRACT The adenylate cyclase (CyaA) of Bordetella pertussisdelivers the N-terminal catalytic domain into the cytosol of a large number of eukaryotic cells, in particular, professional antigen-presenting cells. This allows the delivery of CD8+T-cell epitopes to the major histocompatibility complex class I presentation pathway. We have previously shown that immunization of mice with CyaA carrying a single CD8+ T-cell epitope leads to antiviral protection as well as to protective and therapeutic antitumor immunity associated with the induction of specific cytotoxic T-lymphocyte (CTL) responses. Here, we evaluated the capacity of CyaA carrying one to four copies of the CD8+ CD4+T-cell epitope from the nucleoprotein of the lymphocytic choriomeningitis virus to induce T-cell responses. Both CTL and Th1-like specific responses were detected in mice immunized with recombinant CyaA with or without adjuvant. Although the insertion of the larger peptides resulted in partial loss of the invasive capacity of recombinant CyaA, insertion of several copies of the same epitope led to a strong enhancement of Th1 responses and, to a lesser degree, CTL responses. These results underscore the potency of CyaA for vaccine design with a new impact on diseases in which the Th1 response has been described to have a beneficial effect.

scholarly journals Immunization with a Circumsporozoite Epitope Fused to Bordetella pertussis Adenylate Cyclase in Conjunction with Cytotoxic T-Lymphocyte-Associated Antigen 4 Blockade Confers Protection against Plasmodium berghei Liver-Stage Malaria

2006 ◽  
Vol 74 (4) ◽  
pp. 2277-2285 ◽  
Author(s):  
Susanne Tartz ◽  
Jana Kamanova ◽  
Marcela Simsova ◽  
Peter Sebo ◽  
Stefanie Bolte ◽  
...  
Keyword(s):  
T Cell ◽  
Adenylate Cyclase ◽  
Bordetella Pertussis ◽  
Plasmodium Berghei ◽  
Catalytic Domain ◽  
T Cell Response ◽  
Specific Response ◽  
T Cell Epitopes ◽  
Presentation Pathway ◽  
Boost Immunization

ABSTRACTThe adenylate cyclase toxoid (ACT) ofBordetella pertussisis capable of delivering its N-terminal catalytic domain into the cytosol of CD11b-expressing professional antigen-presenting cells such as myeloid dendritic cells. This allows delivery of CD8+T-cell epitopes to the major histocompatibility complex (MHC) class I presentation pathway. Recombinant detoxified ACT containing an epitope of thePlasmodium bergheicircumsporozoite protein (CSP), indeed, induced a specific CD8+T-cell response in immunized mice after a single application, as detected by MHC multimer staining and gamma interferon (IFN-γ) ELISPOT assay. This CSP-specific response could be significantly enhanced by prime-boost immunization with recombinant ACT in combination with anti-CTLA-4 during the boost immunization. This increased response was accompanied by complete protection in a number of mice after a challenge withP. bergheisporozoites. Transient blockade of CTLA-4 may overcome negative regulation and hence provide a strategy to enhance the efficacy of a vaccine by amplifying the number of responding T cells.

scholarly journals Delivery of Multiple Epitopes by Recombinant Detoxified Adenylate Cyclase of Bordetella pertussisInduces Protective Antiviral Immunity

2001 ◽  
Vol 75 (16) ◽  
pp. 7330-7338 ◽  
Author(s):  
Catherine Fayolle ◽  
Adriana Osickova ◽  
Radim Osicka ◽  
Thomas Henry ◽  
Marie-Jésus Rojas ◽  
...  
Keyword(s):  
T Cell ◽  
Adenylate Cyclase ◽  
Catalytic Domain ◽  
Cytotoxic T Lymphocyte ◽  
Antigen Presenting Cells ◽  
T Cell Epitopes ◽  
Antigen Presenting ◽  
Ctl Responses

ABSTRACT CyaA, the adenylate cyclase toxin from Bordetella pertussis, can deliver its N-terminal catalytic domain into the cytosol of a large number of eukaryotic cells and particularly into professional antigen-presenting cells. We have previously identified within the primary structure of CyaA several permissive sites at which insertion of peptides does not alter the ability of the toxin to enter cells. This property has been exploited to design recombinant CyaA toxoids capable of delivering major histocompatibility complex (MHC) class I-restricted CD8+ T-cell epitopes into antigen-presenting cells and to induce specific CD8+cytotoxic T-lymphocyte (CTL) responses in vivo. Here we have explored the capacity of the CyaA vector carrying several different CD8+ T-cell epitopes to prime multiple CTL responses. The model vaccine consisted of a polyepitope made of three CTL epitopes from lymphocytic choriomeningitis virus (LCMV), the V3 region of human immunodeficiency virus gp120, and chicken ovalbumin, inserted at three different sites of the catalytic domain of genetically detoxified CyaA. Each of these epitopes was processed on delivery by CyaA and presented in vitro to specific T-cell hybridomas. Immunization of mice by CyaA toxoids carrying the polyepitope lead to the induction of specific CTL responses for each of the three epitopes, as well as to protection against a lethal viral challenge. Moreover, mice primed against the vector by mock CyaA or a recombinant toxoid were still able to develop strong CTL responses after subsequent immunization with a recombinant CyaA carrying a foreign CD8+ CTL epitope. These results highlight the potency of the adenylate cyclase vector for induction of protective CTL responses with multiple specificity and/or broad MHC restriction.

scholarly journals In vivo induction of CTL responses by recombinant adenylate cyclase ofBordetella pertussiscarrying multiple copies of a viral CD8+T-cell epitope

1999 ◽  
Vol 26 (2) ◽  
pp. 167-173 ◽  
Author(s):  
Peter Å ebo ◽  
Zohra Moukrim ◽  
MiloÅ¡ Kalhous ◽  
Niels Schaft ◽  
Gilles Dadaglio ◽  
...  
Keyword(s):  
T Cell ◽  
Adenylate Cyclase ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Epitope ◽  
Multiple Copies ◽  
In Vivo Induction ◽  
Ctl Responses

scholarly journals Delivery of CD8+ T-Cell Epitopes into Major Histocompatibility Complex Class I Antigen Presentation Pathway by Bordetella pertussis Adenylate Cyclase: Delineation of Cell Invasive Structures and Permissive Insertion Sites

2000 ◽  
Vol 68 (1) ◽  
pp. 247-256 ◽  
Author(s):  
Radim Osička ◽  
Adriana Osičková ◽  
Tümay Basar ◽  
Pierre Guermonprez ◽  
Marie Rojas ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Adenylate Cyclase ◽  
Mhc Class I ◽  
Bordetella Pertussis ◽  
Class I ◽  
T Cell Epitopes ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Presentation Pathway

ABSTRACT Bordetella pertussis adenylate cyclase (AC) toxin-hemolysin (ACT-Hly) can penetrate a variety of eukaryotic cells. Recombinant AC toxoids have therefore been recently used for delivery of CD8+ T-cell epitopes into antigen-presenting cells in vivo and for induction of protective antiviral, as well as therapeutic antitumor cytotoxic T-cell responses. We have explored the carrier potential of the ACT molecule by insertional mutagenesis scanning for new permissive sites, at which integration of two- to nine-residue-long peptides does not interfere with membrane interaction and translocation of ACT. A model CD8+ T-cell epitope of ovalbumin was incorporated at 10 of these permissive sites along the toxin molecule, and the capacity of ACT constructs to penetrate into cell cytosol and deliver the epitope into the major histocompatibility complex (MHC) class I antigen processing and presentation pathway was examined. While all six constructs bearing the epitope within the Hly portion of ACT failed to deliver the epitope to the MHC class I molecules, all four toxoids with inserts within different permissive sites in the AC domain efficiently delivered the epitope into this cytosolic pathway, giving rise to stimulation of a specific CD8+ T-cell hybridoma. The results suggest that, in contrast to the AC domain, the hemolysin moiety of ACT does not reach the cytosolic entry of the MHC class I pathway.

scholarly journals Immunodominance in Mouse and Human CD4+ T-Cell Responses Specific for the Bordetella pertussis Virulence Factor P.69 Pertactin

2008 ◽  
Vol 77 (2) ◽  
pp. 896-903 ◽  
Author(s):  
Rachel M. Stenger ◽  
Martien C. M. Poelen ◽  
Ed E. Moret ◽  
Betsy Kuipers ◽  
Sven C. M. Bruijns ◽  
...  
Keyword(s):  
T Cell ◽  
Bordetella Pertussis ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Cell Immunity ◽  
Hla Dq ◽  
Natural Variants ◽  
Acellular Vaccines

ABSTRACT P.69 pertactin (P.69 Prn), an adhesion molecule from the causative agent of pertussis, Bordetella pertussis, is present in cellular and most acellular vaccines that are currently used worldwide. Although both humoral immunity and cellular immunity directed against P.69 Prn have been implicated in protective immune mechanisms, the identities of CD4+ T-cell epitopes on the P.69 Prn protein remain unknown. Here, a single I-Ad-restricted B. pertussis conserved CD4+ T-cell epitope at the N terminus of P.69 Prn was identified by using a BALB/c T-cell hybridoma. The epitope appeared immunodominant among four other minor strain-conserved P.69 Prn epitopes recognized after vaccination and B. pertussis infection, and it was capable of evoking a Th1/Th17-type cytokine response. B. pertussis P.69 Prn immune splenocytes did not cross-react with natural variants of the epitope as present in Bordetella parapertussis and Bordetella bronchiseptica. Finally, it was found that the immunodominant P.69 Prn epitope is broadly recognized in the human population by CD4+ T cells in an HLA-DQ-restricted manner. During B. pertussis infection, the epitope was associated with a Th1-type CD4+ T-cell response. Hence, this novel P.69 Prn epitope is involved in CD4+ T-cell immunity after B. pertussis vaccination and infection in mice and, more importantly, in humans. Thus, it may provide a useful tool for the evaluation of the type, magnitude, and maintenance of B. pertussis-specific CD4+ T-cell mechanisms in preclinical and clinical vaccine studies.

scholarly journals Mining the capacity of human-associated microorganisms to trigger rheumatoid arthritis—A systematic immunoinformatics analysis of T cell epitopes

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253918
Author(s):  
Jelena Repac ◽  
Marija Mandić ◽  
Tanja Lunić ◽  
Bojan Božić ◽  
Biljana Božić Nedeljković
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
De Novo ◽  
Molecular Mimicry ◽  
Sequence Similarity ◽  
Cell Epitope ◽  
Homology Search ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Painful Condition

Autoimmune diseases, often triggered by infection, affect ~5% of the worldwide population. Rheumatoid Arthritis (RA)–a painful condition characterized by the chronic inflammation of joints—comprises up to 20% of known autoimmune pathologies, with the tendency of increasing prevalence. Molecular mimicry is recognized as the leading mechanism underlying infection-mediated autoimmunity, which assumes sequence similarity between microbial and self-peptides driving the activation of autoreactive lymphocytes. T lymphocytes are leading immune cells in the RA-development. Therefore, deeper understanding of the capacity of microorganisms (both pathogens and commensals) to trigger autoreactive T cells is needed, calling for more systematic approaches. In the present study, we address this problem through a comprehensive immunoinformatics analysis of experimentally determined RA-related T cell epitopes against the proteomes of Bacteria, Fungi, and Viruses, to identify the scope of organisms providing homologous antigenic peptide determinants. By this, initial homology screening was complemented with de novo T cell epitope prediction and another round of homology search, to enable: i) the confirmation of homologous microbial peptides as T cell epitopes based on the predicted binding affinity to RA-related HLA polymorphisms; ii) sequence similarity inference for top de novo T cell epitope predictions to the RA-related autoantigens to reveal the robustness of RA-triggering capacity for identified (micro/myco)organisms. Our study reveals a much larger repertoire of candidate RA-triggering organisms, than previously recognized, providing insights into the underestimated role of Fungi in autoimmunity and the possibility of a more direct involvement of bacterial commensals in RA-pathology. Finally, our study pinpoints Endoplasmic reticulum chaperone BiP as the most potent (most likely mimicked) RA-related autoantigen, opening an avenue for identifying the most potent autoantigens in a variety of different autoimmune pathologies, with possible implications in the design of next-generation therapeutics aiming to induce self-tolerance by affecting highly reactive autoantigens.

scholarly journals In Silico Identification and in Vitro Analysis of B and T-Cell Epitopes of the Black Turtle Bean (Phaseolus Vulgaris L.) Lectin

2018 ◽  
Vol 49 (4) ◽  
pp. 1600-1614 ◽  
Author(s):  
Shudong He ◽  
Jinlong Zhao ◽  
Walid Elfalleh ◽  
Mohamed Jemaà ◽  
Hanju  Sun ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cell ◽  
Phaseolus Vulgaris ◽  
B Cell ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Phaseolus Vulgaris L ◽  
B Cell Epitopes ◽  
B Cell Epitope

Background/Aims: The incidence of lectin allergic disease is increasing in recent decades, and definitive treatment is still lacking. Identification of B and T-cell epitopes of allergen will be useful in understanding the allergen antibody responses as well as aiding in the development of new diagnostics and therapy regimens for lectin poisoning. In the current study, we mainly addressed these questions. Methods: Three-dimensional structure of the lectin from black turtle bean (Phaseolus vulgaris L.) was modeled using the structural template of Phytohemagglutinin from P. vulgaris (PHA-E, PDB ID: 3wcs.1.A) with high identity. The B and T-cell epitopes were screened and identified by immunoinformatics and subsequently validated by ELISA, lymphocyte proliferation and cytokine profile analyses. Results: Seven potential B-cell epitopes (B1 to B7) were identified by sequence and structure based methods, while three T-cell epitopes (T1 to T3) were identified by the predictions of binding score and inhibitory concentration. The epitope peptides were synthesized. Significant IgE binding capability was found in B-cell epitopes (B2, B5, B6 and B7) and T2 (a cryptic B-cell epitope). T1 and T2 induced significant lymphoproliferation, and the release of IL-4 and IL-5 cytokine confirmed the validity of T-cell epitope prediction. Abundant hydrophobic amino acids were found in B-cell epitope and T-cell epitope regions by amino acid analysis. Positively charged amino acids, such as His residue, might be more favored for B-cell epitope. Conclusion: The present approach can be applied for the identification of epitopes in novel allergen proteins and thus for designing diagnostics and therapies in lectin allergy.

Sign in / Sign up

Export Citation Format

Share Document