DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8
            <sup>+</sup>
            T cells in a spectrum of human MHC I haplotypes

Bozzacco, Leonia; Trumpfheller, Christine; Siegal, Frederick P.; Mehandru, Saurabh; Markowitz, Martin; Carrington, Mary; Nussenzweig, Michel C.; Piperno, Angela Granelli; Steinman, Ralph M.

doi:10.1073/pnas.0610383104

Cited by 217 publications

(190 citation statements)

References 56 publications

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“…A fascinating recent example has been provided in the case of HIV gag protein delivered within antibodies to human DEC-205. For the first time, it has been shown that cross-presentation is able to extract defined peptides for presentation to CD8 + T cells across a spectrum of MHC haplotypes [94]. I am excited about this new field of receptor-based antigen targeting to DC, which allows one to analyze DC function -both antigen processing and subsequent interactions with lymphocytes -directly in vivo, without the need for cell isolation.…”

Section: New Developments In Antigen Handling and Maturation Of Dendrmentioning

confidence: 99%

Dendritic cells: Understanding immunogenicity

2007

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The impetus for the discovery of dendritic cells in 1972 was to understand immunogenicity, the capacity of an antigenic substance to provoke immunity. During experiments to characterize "accessory" cells that enhanced immunity, we spotted unusual stellate cells in mouse spleen. They had a distinct capacity to form and retract processes or dendrites and were named dendritic cells (DC). DC proved to be different from other cell types and to be peculiarly immunogenic when loaded with antigens. When Langerhans cells were studied, immunogenicity was found to involve two steps: antigen presentation by immature DC and maturation to elicit immunity. Antigenbearing DC were also immunogenic in vivo and were therefore termed "nature's adjuvants". Several labs then learned to generate large numbers of DC from progenitors, which accelerated DC research. Tolerogenicity via DC, including the control of foxp3 + suppressor T cells, was recently discovered. Two areas of current research that I find intriguing are to identify mechanisms for antigen uptake and processing, and for the control of different types of immunity and tolerance. These subjects should be studied in vivo with clinically relevant antigens, so that the activities of DC can be better integrated into the prevention and treatment of disease in patients.

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Section: New Developments In Antigen Handling and Maturation Of Dendrmentioning

confidence: 99%

Dendritic cells: Understanding immunogenicity

2007

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“…To assess the capacity of the 3D6 and 3G9 mAbs to mediate cross-presentation, we studied HIV-primed CD8 ϩ T cells from HIV-infected individuals as previously described, 11 since we were unable to prime large numbers of CD8 ϩ T cells to HIV Gag in Acetone-fixed cryostat sections of subcutaneous lymph nodes were stained with 3G9 mAb, followed by secondary PE-conjugated antihuman IgG, and FITC-anti-B220 to discriminate B and T areas. Images were taken 200ϫ magnification, but the region with the asterisk (*) is magnified 400ϫ on the right using a Molecular Devices OlympusAX70 deconvolution microscope (Olympus) running METAMORPH Meta Imaging 3.0 (Universal Imaging Corporaration).…”

Section: Cross-presentation Of Human Anti-hdec205 Hiv Gag To Gag Primmentioning

confidence: 99%

Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti–human DEC205 monoclonal antibody

Cheong

Choi

Vitale

et al. 2010

Blood

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109

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Protein vaccines for T-cell immunity are not being prioritized because of poor immunogenicity. To overcome this hurdle, proteins are being targeted to maturing dendritic cells (DCs) within monoclonal antibodies (mAbs) to DC receptors. To extend the concept to humans, we immunized human immunoglobulin-expressing mice with human DEC205 (hDEC205) extracellular domain. 3D6 and 3G9 mAbs were selected for high-affinity binding to hDEC205. In addition, CD11c promoter hDEC205 transgenic mice were generated, and 3G9 was selectively targeted to DCs in these animals. When mAb heavy chain was engineered to express HIV Gag p24, the fusion mAb induced interferon-␥-and interleukin-2-producing CD4 ؉ T cells in hDEC205 transgenic mice, if polynocinic polycytidylic acid was coadministered as an adjuvant. The T-cell response was broad, recognizing at least 3 Gag peptides, and high titers of antihuman immunoglobulin G antibody were made. Anti-hDEC205 also improved the cross-presentation of Gag to primed CD8 ؉ T cells from HIV-infected individuals. In all tests, 3D6 and 3G9 targeting greatly enhanced immunization relative to nonbinding control mAb. These results provide preclinical evidence that in vivo hDEC205 targeting increases the efficiency with which proteins elicit specific immunity, setting the stage for proof-of-concept studies of these new protein vaccines in human subjects. (Blood. 2010;116(19):3828-3838)

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“…Nevertheless, these cell-based vaccines present some disadvantages, mainly related to their cost and the variability of the preparations between different patients. Engineered cell-free vaccine antigens that specifically target DC in vivo have also been used [24]. One of the most frequent approaches for vaccination in cancer is based on the use of 8-10 aa-long minimal MHC I-binding peptides derived from TAA.…”

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confidence: 99%

Long‐lasting cross‐presentation of tumor antigen in human DC

et al. 2009

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DC cross-present exogenous antigens on MHC class I molecules, a process required for the onset of anti-tumor immune responses. In order to study the cross-presentation of tumor antigens by human DC, we compared the pathways of cross-presentation of long peptides requiring internalization and intracellular processing with the direct presentation of short peptides, which does not require intracellular processing. We found that, after brief incubations with DC, short peptides were presented to CD8 1 T cells with higher efficiencies than long peptides. After longer times of chase in the absence of peptide, however, the efficiency of presentation of the two types of peptides was reversed. After 2-3 days, DC pulsed with long peptides still activated T cells efficiently, while DC pulsed with short peptides failed to do so. Long-lasting presentation of the long peptides was, at least in part, due to a stored persistent pool of antigen, which was still available for loading on MHC class I molecules after several days of chase. These results show that the use of long synthetic peptides allows the efficient, long-lasting, presentation of tumor antigens, suggesting that long peptides represent an interesting approach for active anti-tumor vaccination.Key words: Cross-presentation . CTL . DC . Long peptides . Melanoma-associated antigen Supporting Information available online IntroductionAdaptative immune responses, especially through CD8 1 T cells, can induce the rejection of solid tumors [1][2][3]. Endogenously expressed tumor-associated antigens (TAA) expressed in tumor cells are recognized by CTL through cognate interactions of the TCR with class I MHC molecules associated with 8-10 amino acid long antigenic peptides. These tumor cell/T-cell interactions, however, are not sufficient to activate naïve T lymphocytes and to induce a memory response. Indeed, professional APC are required for the induction of effector and memory tumor-specific immune responses [4,5]. As most often APC do not endogenously express TAA, uptake and presentation of antigen via an exogenous pathway is required. This so-called ''cross-presentation'' pathway is mainly performed by DC [6,7]. Following the initial observations of cross-priming of T cells by bone-marrowderived cells [8,9], numerous studies investigated the role of cross-priming in the induction of anti-tumor immune responses [10][11][12][13][14] and the strategies to manipulate cross-priming to induce and amplify tumor-specific immune responses [15][16][17][18][19]. Because 380they display a unique capacity to efficiently cross-present exogenous antigens and to prime naïve CD8 1 T cells, DC are good candidates for cancer immunotherapy. The DC-based cancer vaccines that have been tested successfully in mouse models include DC loaded with different forms of tumor antigens, including short peptides, tumor extracts, tumor-derived membrane vesicles and tumor-derived RNA [20][21][22][23]. Nevertheless, these cell-based vaccines present some disadvantages, mainly related to their cost and the...

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DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8 ⁺ T cells in a spectrum of human MHC I haplotypes

Cited by 217 publications

References 56 publications

Dendritic cells: Understanding immunogenicity

Dendritic cells: Understanding immunogenicity

Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti–human DEC205 monoclonal antibody

Long‐lasting cross‐presentation of tumor antigen in human DC

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DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8 + T cells in a spectrum of human MHC I haplotypes

Cited by 217 publications

References 56 publications

Dendritic cells: Understanding immunogenicity

Dendritic cells: Understanding immunogenicity

Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti–human DEC205 monoclonal antibody

Long‐lasting cross‐presentation of tumor antigen in human DC

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DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8 ⁺ T cells in a spectrum of human MHC I haplotypes