New tools for antigen delivery to the MHC class I pathway

Morón, Gabriel; Dadaglio, Gilles; Leclerc, Claude

doi:10.1016/j.it.2003.11.008

Cited by 98 publications

(68 citation statements)

References 51 publications

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“…Detailed characterization of the mechanisms underlying the entry of CyaA into target cells and delivery of the cargo epitopes for presentation allowed corroboration of the previous observations that CyaA can translocate its AC domain into target cell cytosol directly across the plasma membrane without the need for endocytosis (11,21,52 and that this intoxication is very fast (52). However, our results show that unlike MHC I-restricted presentation, MHC II-restricted presentation of CyaA depends on its internalization through a clathrin-mediated endocytosis.…”

Section: Discussionsupporting

confidence: 87%

Antigen Targeting to CD11b Allows Efficient Presentation of CD4+ and CD8+ T Cell Epitopes and In Vivo Th1-Polarized T Cell Priming

Schlecht

Loucká

Najar

et al. 2004

The Journal of Immunology

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Bordetella pertussis adenylate cyclase (CyaA) is an invasive bacterial toxin that delivers its N-terminal catalytic domain into the cytosol of eukaryotic cells bearing the αMβ2 integrin (CD11b/CD18), such as myeloid dendritic cells. This allows use of engineered CyaA for targeted delivery of CD8+ T cell epitopes into the MHC class I pathway of APC and induction of robust and protective cytotoxic responses. In this study, we demonstrate that CyaA can efficiently codeliver both a CD8+ T cell epitope (OVA257–264) and a CD4+ T cell epitope (MalE100–114) into, respectively, the conventional cytosolic or endocytic routes of processing of murine bone marrow-derived dendritic cells. Upon CyaA delivery, a strong potentiation of the MalE100–114 CD4+ T cell epitope presentation is observed as compared with the MalE protein, which depends on CyaA interaction with its CD11b receptor and its subsequent clathrin-mediated endocytosis. In vivo, CyaA induces strong and specific Th1 CD4+ and CD8+ T cell responses against, respectively, the MalE100–114 and OVA257–264 epitopes. These results underscore the potency of CyaA for design of new vaccines.

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Section: Discussionsupporting

confidence: 87%

Antigen Targeting to CD11b Allows Efficient Presentation of CD4+ and CD8+ T Cell Epitopes and In Vivo Th1-Polarized T Cell Priming

Schlecht

Loucká

Najar

et al. 2004

The Journal of Immunology

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“…39,40 By constructing recombinant protein and cell-penetrating peptide, different proteins and polypeptides were delivered into a variety of cells in vivo and in vitro. 41,42 HBcAg 18-27 epitope has been shown to be able to induce HBV-specific CTL response and thus is a potential for the therapeutic design of chronic HBV infection. 16,17 In the present study, we expressed HBcAg [18][19][20][21][22][23][24][25][26][27] included the complete amino-acid sequences that were fused with CTP and Tapasin.…”

Section: Ctp-hbcag 18-27 -Tapasin Induces Hbv-specific Ctls X Chen Et Almentioning

confidence: 99%

Tapasin modification on the intracellular epitope HBcAg18–27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo

Chen

Tang

Zhang

et al. 2014

Laboratory Investigation

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HBV-specific cytotoxic T-lymphocyte (CTL) activity has a very important role in hepatitis B virus clearance. Present studies suggest that Tapasin, a endoplasmic reticulum (ER) chaperone, stabilizes the peptide-receptive MHC I conformation, allowing peptide exchange and increasing more peptides to be translocated into the ER. We have previously testified that cytoplasmic transduction peptide (CTP)-HBcAg 18-27 -Tapasin fusion protein could enter cytoplasm of dendritic cells, and enhance T cells' response to generate specific CTLs efficiently in vitro. In the present study, we evaluated specific immune responses of CTP-HBcAg 18-27 -Tapasin fusion protein in HLA-A2 transgenic mice (H-2K b ) and anti-viral ability in HBV transgenic mice, and explored the mechanisms probably involved in. The studies showed that CTP-HBcAg 18-27 -Tapasin not only increased production of cytokine IFN-g and interleukin-2 (IL-2), compared with CTP-HBcAg 18-27 , HBcAg 18-27 -Tapasin, and PBS, but also significantly induced the higher percentages of IFN-g þ CD8 þ T cells and specific CTL responses in HLA-A2 transgenic mice. Moreover, enhancement of specific CTL activity induced by the fusion protein reduced HBV DNA and hepatitis B surface antigen (HBsAg) levels and decreased the expression of HBsAg and hepatitis B core antigen (HBcAg) in liver tissue of HBV transgenic mice. In addition, CTP-HBcAg 18-27 -Tapasin could upregulate the expression of JAK2, Tyk2, STAT1, and STAT4 in T lymphocytes in HLA-A2 transgenic mice splenocytes. However, there was no significant difference on the expressions of JAK1, JAK3, and STAT6 between each group. In conclusion, CTP-HBcAg 18-27 -Tapasin fusion protein could enhance not only the percentages of CTLs but also induce robust specific CTL activity and inhibits hepatitis B virus replication in vivo, which was associated with activation of the JAK/STAT signaling pathway. Hepatitis B virus (HBV) infection remains a global problem, despite the effectiveness of the HBV vaccines in preventing infection. Although the factors that contribute to the clearance of the virus in acute self-limiting HBV infection or to the persistence of the virus in chronic HBV infection are not completely clear, increasing evidence suggests that host immune responses are an important factor in determining the outcome of HBV infection. 1,2 Acute individuals develop a strong, polyclonal, multispecific cytotoxic T-lymphocyte (CTL) response and a polyclonal T helper (Th) cell response to the virus typically, while these responses are markedly attenuated in chronically infected patients. 3,4 Persistent HBV infection is characterized by a weak adaptive immune response, thought to be due to inefficient CD4 þ T-cell priming in the early stage of virus infection and subsequent development of a quantitatively and qualitatively ineffective CD8 þ T-cell response. Studies of HBV infection in woodchucks and chimpanzees, as well as patients, are suggesting that multiple and frequent administration of the vaccine may be advisable in treatment of chronic...

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“…Use of CpG oligonucleotides as vaccine adjuvants can also elicit cross-priming when high doses of Ag are administered (14,31,32). However, the most efficient and robust CD8 ϩ T cell responses are currently generated by immunization with replicating vaccines, including both viral and bacterial vectored vaccines (7,8,11,(33)(34)(35)(36)(37)(38)(39).…”

Section: S Timulation Of Innate Immunity Is Necessary For Generationmentioning

confidence: 99%

Efficient Immunization and Cross-Priming by Vaccine Adjuvants Containing TLR3 or TLR9 Agonists Complexed to Cationic Liposomes

Zaks

Jordan

Guth³

et al. 2006

The Journal of Immunology

227

187

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Complexing TLR9 agonists such as plasmid DNA to cationic liposomes markedly potentiates their ability to activate innate immunity. We therefore reasoned that liposomes complexed with DNA or other TLR agonists could be used as effective vaccine adjuvants. To test this hypothesis, the vaccine adjuvant effects of liposomes complexed to TLR agonists were assessed in mice. We found that liposomes complexed to nucleic acids (liposome-Ag-nucleic acid complexes; LANAC) were particularly effective adjuvants for eliciting CD4+ and CD8+ T cell responses against peptide and protein Ags. Notably, LANAC containing TLR3 or TLR9 agonists effectively cross-primed CD8+ T cell responses against even low doses of protein Ags, and this effect was independent of CD4+ T cell help. Ag-specific CD8+ T cells elicited by LANAC adjuvants were functionally active and persisted for long periods of time in tissues. In a therapeutic tumor vaccine model, immunization with the melanoma peptide trp2 and LANAC adjuvant controlled the growth of established B16 melanoma tumors. In a prophylactic vaccine model, immunization with the Mycobacterium tuberculosis protein ESAT-6 with LANAC adjuvant elicited significant protective immunity against aerosol challenge with virulent M. tuberculosis. These results suggest that certain TLR agonists can be combined with cationic liposomes to produce uniquely effective vaccine adjuvants capable of eliciting strong T cell responses against protein and peptide Ags.

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New tools for antigen delivery to the MHC class I pathway

Cited by 98 publications

References 51 publications

Antigen Targeting to CD11b Allows Efficient Presentation of CD4+ and CD8+ T Cell Epitopes and In Vivo Th1-Polarized T Cell Priming

Antigen Targeting to CD11b Allows Efficient Presentation of CD4+ and CD8+ T Cell Epitopes and In Vivo Th1-Polarized T Cell Priming

Tapasin modification on the intracellular epitope HBcAg18–27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo

Efficient Immunization and Cross-Priming by Vaccine Adjuvants Containing TLR3 or TLR9 Agonists Complexed to Cationic Liposomes

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