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{"title"=>"CD8+ T cell priming by dendritic cell vaccines requires antigen transfer to endogenous antigen presenting cells", "type"=>"journal", "authors"=>[{"first_name"=>"Alice W.", "last_name"=>"Yewdall", "scopus_author_id"=>"25923193600"}, {"first_name"=>"Scott B.", "last_name"=>"Drutman", "scopus_author_id"=>"12761808200"}, {"first_name"=>"Felecia", "last_name"=>"Jinwala", "scopus_author_id"=>"36237610900"}, {"first_name"=>"Keith S.", "last_name"=>"Bahjat", "scopus_author_id"=>"6505844341"}, {"first_name"=>"Nina", "last_name"=>"Bhardwaj", "scopus_author_id"=>"56992503500"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"20585396", "doi"=>"10.1371/journal.pone.0011144", "sgr"=>"77955261234", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "scopus"=>"2-s2.0-77955261234", "issn"=>"19326203", "pui"=>"359293480"}, "id"=>"a7b208e8-98dc-33cc-8d7f-a14e0c3e0a33", "abstract"=>"BACKGROUND Immunotherapeutic strategies to stimulate anti-tumor immunity are promising approaches for cancer treatment. A major barrier to their success is the immunosuppressive microenvironment of tumors, which inhibits the functions of endogenous dendritic cells (DCs) that are necessary for the generation of anti-tumor CD8+ T cells. To overcome this problem, autologous DCs are generated ex vivo, loaded with tumor antigens, and activated in this non-suppressive environment before administration to patients. However, DC-based vaccines rarely induce tumor regression. METHODOLOGY/PRINCIPAL FINDINGS We examined the fate and function of these DCs following their injection using murine models, in order to better understand their interaction with the host immune system. Contrary to previous assumptions, we show that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells. CONCLUSIONS/SIGNIFICANCE This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches should focus on creating DC vaccines that are more effective at directly priming T cells, or abrogating the tumor induced suppression of endogenous DCs.", "link"=>"http://www.mendeley.com/research/cd8-t-cell-priming-dendritic-cell-vaccines-requires-antigen-transfer-endogenous-antigen-presenting-c", "reader_count"=>66, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>6, "Student > Doctoral Student"=>4, "Researcher"=>21, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>2, "Student > Master"=>8, "Other"=>3, "Student > Bachelor"=>1, "Lecturer > Senior Lecturer"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>6, "Student > Doctoral Student"=>4, "Researcher"=>21, "Student > Ph. D. Student"=>17, "Student > Postgraduate"=>2, "Student > Master"=>8, "Other"=>3, "Student > Bachelor"=>1, "Lecturer > Senior Lecturer"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>35, "Medicine and Dentistry"=>9, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1, "Computer Science"=>3, "Immunology and Microbiology"=>10}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>9}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>10}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>35}, "Computer Science"=>{"Computer Science"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"New Zealand"=>1, "United States"=>2, "Norway"=>1, "Ireland"=>1, "United Kingdom"=>1, "Portugal"=>1}, "group_count"=>3}

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• {"month"=>"2", "year"=>"2019", "pdf_views"=>"6", "xml_views"=>"1", "html_views"=>"29"}
• {"month"=>"3", "year"=>"2019", "pdf_views"=>"18", "xml_views"=>"0", "html_views"=>"54"}
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• {"month"=>"8", "year"=>"2019", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"34"}
• {"month"=>"9", "year"=>"2019", "pdf_views"=>"2", "xml_views"=>"1", "html_views"=>"30"}

Figshare

• {"files"=>["https://ndownloader.figshare.com/files/845164"], "description"=>"<p>(<b><i>A</i></b><b>-</b><b><i>B</i></b><b>, </b><b><i>D</i></b>) CD11c-DTR BMCs were treated with diptheria toxin (DT) on days −4, −1, and 2 relative to the day of vaccination. Naïve transgenic CD8+ T cells were adoptively transferred intravenously on day −1. Antigen-specific T cell responses were analyzed on day 7 post-vaccination. (<b><i>B</i></b>) Mice previously injected with naïve OT-1 CD8+ T cells (5,000 cells/mouse) were left untreated or vaccinated with one of the following: attenuated <i>Lm</i>OVA (1×10⁶ CFU/mouse), LPS-matured B6 DCs pulsed with 10 ng/ml of OVA_257–264 peptide (OVA₂₅₇+DCs, 0.5×10⁶ cells/mouse), or LPS-matured ActOVA DCs (0.5×10⁶ cells/mouse). The percentages of OVA_256–264-tetramer positive and of IFN-γ- and TNF-producing CD8+ T cells are shown (data are mean ± s.d. for 4 to 9 mice per group as indicated). (<b><i>C</i></b>) ActOVA DC and peptide-DCs were cultured in the presence of proteosome inhibitors and the H-2K^b-restricted NP_324–332 peptides (1 ug/ml). Acid washing elutes surface MHC-bound peptides and was used to confirm the inhibition of antigen processing by the inhibitors. Shown are the cell surface levels of OVA_257–264-MHC class I complexes. (<b><i>D</i></b>) DT-treated or untreated CD11c-DTR BMCs were injected with 10,000 LCMV P14 T cells, followed by vaccination with B6 bone marrow derived DCs pulsed with 1 ug/ml of LCMV gp_33–41 peptides (peptide-DCs, 0.5×10⁶ cells/mouse). On Day 7 post-vaccination, the frequencies of IFN-γ producing CD8+ T cells (data are mean ± s.d. of 5 mouse per group) were determined.</p>", "links"=>[], "tags"=>["dcs", "recipients", "antigens", "derived", "dc", "activating", "cells"], "article_id"=>515616, "categories"=>["Immunology"], "users"=>["Alice W. Yewdall", "Scott B. Drutman", "Felecia Jinwala", "Keith S. Bahjat", "Nina Bhardwaj"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0011144.g004", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Endogenous_CD11c_high_DCs_are_recipients_of_antigens_derived_from_DC_vaccines_that_are_essential_for_activating_na_239_ve_CD8_T_cells_in_vivo_/515616", "title"=>"Endogenous CD11c^high DCs are recipients of antigens derived from DC vaccines, that are essential for activating naïve CD8+ T cells <i>in vivo.</i>", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-06-16 01:33:36"}
• {"files"=>["https://ndownloader.figshare.com/files/844807"], "description"=>"<p>(<b><i>A</i></b>) Wild type C57BL/6 (B6) mice were vaccinated with either attenuated <i>Lm</i>OVA (1×10⁶ CFU/mouse), OVA_257–264 (100 ng/ml)–pulsed LPS-matured B6 DCs (peptide-DCs, 1×10⁶ cells/mouse), or unpulsed LPS-matured B6 DCs (DC alone, 1×10⁶ cells/mouse). On day 7, the percentage of IFN-γ producing CD8+ T cells was determined (horizontal bar  =  mean). (<b><i>B</i></b>) B6→B6 (B6) and Bm1→B6 (Bm1) marrow chimeras (BMCs) were adoptively transferred with 5,000 naïve OT-1 T cells and vaccinated the following day with <i>Lm</i>OVA (1×10⁶ CFU/mouse), peptide-DCs (1×10⁶ cells/mouse), or DCs alone (1×10⁶ cells/mouse). The immune response was assessed on days 7 and 18 post-vaccination. (<b><i>C</i></b>) Antigen-specific IFN-γ production by splenic CD8+ T cells was measured on day 7. Data are mean + s.d. for 3 mice per group and are representative of 3 experiments. (<b><i>D</i></b>) <i>In vivo</i> killing of OVA_257–264 peptide coated target cells in the spleen between days 18 and 20 was assessed. Specific killing was normalized to the internal control of target cells coated with an irrelevant peptide from the Sendai virus nucleoprotein, NP_324–332. Data are mean ± s.d. for 3 mice per group and are representative of 2 experiments.</p>", "links"=>[], "tags"=>["dc", "vaccines", "cells", "induce", "maximal"], "article_id"=>515259, "categories"=>["Immunology"], "users"=>["Alice W. Yewdall", "Scott B. Drutman", "Felecia Jinwala", "Keith S. Bahjat", "Nina Bhardwaj"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0011144.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Peptide_pulsed_DC_vaccines_require_help_from_host_immune_cells_to_induce_a_maximal_CD8_T_cell_response_/515259", "title"=>"Peptide-pulsed DC vaccines require help from host immune cells to induce a maximal CD8+ T cell response.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-06-16 01:27:39"}
• {"files"=>["https://ndownloader.figshare.com/files/420710", "https://ndownloader.figshare.com/files/420749", "https://ndownloader.figshare.com/files/420860", "https://ndownloader.figshare.com/files/420927", "https://ndownloader.figshare.com/files/420997", "https://ndownloader.figshare.com/files/421141"], "description"=>"<div><h3>Background</h3><p>Immunotherapeutic strategies to stimulate anti-tumor immunity are promising approaches for cancer treatment. A major barrier to their success is the immunosuppressive microenvironment of tumors, which inhibits the functions of endogenous dendritic cells (DCs) that are necessary for the generation of anti-tumor CD8+ T cells. To overcome this problem, autologous DCs are generated <em>ex vivo</em>, loaded with tumor antigens, and activated in this non-suppressive environment before administration to patients. However, DC-based vaccines rarely induce tumor regression.</p><h3>Methodology/Principal Findings</h3><p>We examined the fate and function of these DCs following their injection using murine models, in order to better understand their interaction with the host immune system. Contrary to previous assumptions, we show that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells.</p><h3>Conclusions/Significance</h3><p>This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches should focus on creating DC vaccines that are more effective at directly priming T cells, or abrogating the tumor induced suppression of endogenous DCs.</p></div>", "links"=>[], "tags"=>["priming", "dendritic", "vaccines", "requires", "antigen", "endogenous", "presenting", "cells"], "article_id"=>143067, "categories"=>["Immunology"], "users"=>["Alice W. Yewdall", "Scott B. Drutman", "Felecia Jinwala", "Keith S. Bahjat", "Nina Bhardwaj"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0011144.s001", "https://dx.doi.org/10.1371/journal.pone.0011144.s002", "https://dx.doi.org/10.1371/journal.pone.0011144.s003", "https://dx.doi.org/10.1371/journal.pone.0011144.s004", "https://dx.doi.org/10.1371/journal.pone.0011144.s005", "https://dx.doi.org/10.1371/journal.pone.0011144.s006"], "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/CD8_T_Cell_Priming_by_Dendritic_Cell_Vaccines_Requires_Antigen_Transfer_to_Endogenous_Antigen_Presenting_Cells/143067", "title"=>"CD8+ T Cell Priming by Dendritic Cell Vaccines Requires Antigen Transfer to Endogenous Antigen Presenting Cells", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-06-16 00:51:07"}
• {"files"=>["https://ndownloader.figshare.com/files/844926"], "description"=>"<p>(<b><i>A</i></b>) By measuring the relative activation of B3Z T cell hybridomas, the cell surface OVA_257–264-MHC complex levels on different LPS-matured bone marrow derived DC conditions were assessed. The DC conditions included LPS-matured B6 DCs, OVA_257–264 (10 ng/ml)–pulsed LPS-matured B6 DCs, and ActOVA DCs. (<b><i>B</i></b>) To determine the ability of these DCs to activate naïve CD8+ T cells <i>in vitro</i>, they were cultured with CFSE-labeled naïve OT-1 T cells at various ratios. On day 3, the percentage of proliferating cells was analyzed by flow cytometry. (<b><i>C</i></b>) B6→B6 (B6) and Bm1→B6 (Bm1) bone marrow chimeras (BMCs) were adoptively transferred with 5,000 naïve OT-1 CD8+ T cells. The next day, these mice were vaccinated intravenously with one of the following: B6 DCs (0.5×10⁶ cells/mouse), attenuated <i>Lm</i>OVA (1×10⁶ CFU/mouse), or ActOVA DCs (0.5×10⁶ cells/mouse). The frequency of OVA_257–264-tetramer positive and IFN-γ producing CD8+ T cells was determined 7 days post-vaccination (mean ± s.d. for 4 mice per group).</p>", "links"=>[], "tags"=>["vaccines", "expressing", "antigens", "delivered", "intravenously", "cells", "maximal", "activation"], "article_id"=>515373, "categories"=>["Immunology"], "users"=>["Alice W. Yewdall", "Scott B. Drutman", "Felecia Jinwala", "Keith S. Bahjat", "Nina Bhardwaj"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0011144.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DC_vaccines_expressing_protein_antigens_delivered_intravenously_require_help_from_host_cells_for_maximal_activation_of_na_239_ve_CD8_T_cells_/515373", "title"=>"DC vaccines expressing protein antigens delivered intravenously require help from host cells for maximal activation of naïve CD8+ T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-06-16 01:29:33"}
• {"files"=>["https://ndownloader.figshare.com/files/845023"], "description"=>"<p>(<b><i>A</i></b>) B6→B6 (B6) and K^bD^b KO→B6 (K^bD^b KO) bone marrow chimeras (BMCs) were adoptively transferred with 5,000 naïve OT-1 CD8+ T cells. The next day, they were vaccinated subcutaneously in the footpad with one of the following: LPS-matured B6 DCs (0.5×10⁶ cells/mouse), attenuated <i>Lm-</i>OVA (1×10⁶ CFU/mouse), or LPS-matured ActOVA DCs (0.5×10⁶ cells/mouse). The frequencies of OVA_257–264-tetramer positive CD8+ T cells in the spleen (individual mice) and draining lymph node (LN, combined value of from mice of each condition) and IFN-γ producing CD8+ T cells in the spleen of each mouse were determined 7 days post-vaccination (data are mean ± s.d. for 4 mice per group). (<b><i>B</i></b>) To track migration of DCs to the draining LN, CFSE-labeled or –unlabeled LPS-matured DCs (1×10⁶ cells/mouse) were injected subcutaneously in the foot pad of naïve mice. The popliteal LNs were removed 2 and 3 days post-injection. Cells were gated on the live (7-AAD negative) and CD11b+ population using flow cytometry to analyze the percentage (0.1–0.3%) of DCs that migrated. (<b><i>C</i></b>) CFSE-labeled CD45.1 donor DCs were injected subcutaneously in the footpad of CD45.1-CD45.2+ wild type mice. Two days later the popliteal LNs were removed and cells were stained with anti-CD45.1 and anti-CD45.2 antibodies.</p>", "links"=>[], "tags"=>["vaccinated", "subcutaneously", "mhc", "cells", "activate"], "article_id"=>515479, "categories"=>["Immunology"], "users"=>["Alice W. Yewdall", "Scott B. Drutman", "Felecia Jinwala", "Keith S. Bahjat", "Nina Bhardwaj"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0011144.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DCs_vaccinated_subcutaneously_require_MHC_class_I_expression_on_the_host_immune_cells_to_fully_activate_na_239_ve_CD8_T_cells_/515479", "title"=>"DCs vaccinated subcutaneously require MHC class I expression on the host immune cells to fully activate naïve CD8+ T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-06-16 01:31:19"}

PMC Usage Stats | Further Information

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