Dataset Information

Adenovirus type-35 vectors block human CD4+ T-cell activation via CD46 ligation.

ABSTRACT: Recombinant adenoviruses (rAds) based on types 5 (rAd5) and 35 (rAd35) have emerged as important vaccine delivery vectors in clinical testing for a variety of pathogens. A major difference between these vectors is their binding to cellular receptors used for infection. Whereas rAd5 binds coxsackie-adenovirus receptor (CAR), rAd35 binds the complement regulatory protein CD46. Although rAd35 infected and phenotypically matured human blood dendritic cells (DCs) more efficiently than rAd5, we show here that rAd35 markedly suppressed DC-induced activation of naive CD4(+) T cells. rAd35 specifically blocked both DCs and anti-CD3/CD28 mAb-induced naive T-cell proliferation and IL-2 production. This effect was also observed in CD4(+) memory T cells but to a lesser extent. The suppression occurred by rAd35 binding to CD46 on T cells and was independent of infection. CD46 engagement with mAb mimicked the effects of rAd35 and also led to deficient NF-?B nuclear translocation. In contrast, rAd5 and rAd35 vectors with ablated CD46 binding did not inhibit T-cell activation. Our findings provide insights into the basic biology of adenoviruses and indicate that CD46 binding may have an impact on the generation of primary CD4(+) T-cell responses by Ad35.

SUBMITTER: Adams WC

PROVIDER: S-EPMC3088631 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Adenovirus type-35 vectors block human CD4+ T-cell activation via CD46 ligation.

Adams William C WC Gujer Cornelia C McInerney Gerald G Gall Jason G D JG Petrovas Constantinos C Karlsson Hedestam Gunilla B GB Koup Richard A RA Loré Karin K

Proceedings of the National Academy of Sciences of the United States of America 20110418 18

Recombinant adenoviruses (rAds) based on types 5 (rAd5) and 35 (rAd35) have emerged as important vaccine delivery vectors in clinical testing for a variety of pathogens. A major difference between these vectors is their binding to cellular receptors used for infection. Whereas rAd5 binds coxsackie-adenovirus receptor (CAR), rAd35 binds the complement regulatory protein CD46. Although rAd35 infected and phenotypically matured human blood dendritic cells (DCs) more efficiently than rAd5, we show h ...[more]

PMID: 21502499

Similar Datasets

Project description:The most advanced malaria vaccine, RTS,S, is comprised of a portion of the Plasmodium falciparum circumsporozoite (CS) protein, fused to and admixed with the hepatitis B virus surface antigen, and an adjuvant [corrected].This vaccine confers short-term protection against malaria infection, with an efficacy of about 50%, and induces particularly B-cell and CD4(+) T-cell responses.In the present study, we tested the hypothesis that the Th1 immune response to CS protein,in particular the CD8(+) T-cell response, which is needed for strong and lasting malaria immunity, is boosted to sustainable levels by adenovirus vectors 35 and 26 with a homologous insert (Ad35.CS/Ad26.CS) [corrected]. In this study, we evaluated immune responses induced with vaccination regimens based on an adjuvant-containing, yeast-produced complete CS protein followed by two recombinant low-seroprevalence adenoviruses expressing P. falciparum CS antigen, Ad35.CS (subgroup B) and Ad26.CS (subgroup D). Our results show that (i) the yeast (Hansenula polymorpha)produced, adjuvanted full-length CS protein is highly potent in inducing high CS-specific humoral responses in mice but produces poor T-cell responses, (ii) the Ad35.CS vector boosts the gamma interferon-positive (IFN-?(+)) CD8(+) T-cell response induced by the CS protein immunization and shifts the immune response toward the Th1 type, and (iii) a three-component heterologous vaccination comprised of a CS protein prime followed by boosts with Ad35.CS and Ad26.CS elicits an even more robust and sustainable IFN-?(+) CD8(+) T-cell response than one- or two-component regimens. The Ad35.CS/Ad26.CS combination boosted particularly the IFN-?(+) and tumor necrosis factor alpha-positive (TNF-?(+)) T cells, confirming the shift of the immune response from the Th2 type to the Th1 type. These results support the notion of first immunizations of infants with an adjuvanted CS protein vaccine, followed by a booster Ad35.CS/Ad26.CS vaccine at a later age, to induce lasting protection against malaria for which the Th1 response and immune memory is required.

Dataset Information

Adenovirus type-35 vectors block human CD4+ T-cell activation via CD46 ligation.

Publications

Adenovirus type-35 vectors block human CD4+ T-cell activation via CD46 ligation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets