CD154 and IL-2 Signaling of CD4+ T Cells Play a Critical Role in Multiple Phases of CD8+ CTL Responses Following Adenovirus Vaccination
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{"title"=>"CD154 and IL-2 Signaling of CD4+ T Cells Play a Critical Role in Multiple Phases of CD8+ CTL Responses Following Adenovirus Vaccination", "type"=>"journal", "authors"=>[{"first_name"=>"Channakeshava", "last_name"=>"Sokke Umeshappa", "scopus_author_id"=>"55377588700"}, {"first_name"=>"Roopa", "last_name"=>"Hebbandi Nanjundappa", "scopus_author_id"=>"55377481900"}, {"first_name"=>"Yufeng", "last_name"=>"Xie", "scopus_author_id"=>"8718526200"}, {"first_name"=>"Andrew", "last_name"=>"Freywald", "scopus_author_id"=>"6506874365"}, {"first_name"=>"Yulin", "last_name"=>"Deng", "scopus_author_id"=>"55261848900"}, {"first_name"=>"Hong", "last_name"=>"Ma", "scopus_author_id"=>"55324750400"}, {"first_name"=>"Jim", "last_name"=>"Xiang", "scopus_author_id"=>"7201547103"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84867172509", "pui"=>"365796779", "doi"=>"10.1371/journal.pone.0047004", "isbn"=>"10.1371/journal.pone.0047004", "sgr"=>"84867172509", "pmid"=>"23071696"}, "id"=>"4d03645d-5e82-3488-88a6-6f878f6cc43d", "abstract"=>"Adenoviral (AdV) vectors represent most commonly utilized viral vaccines in clinical studies. While the role of CD8(+) cytotoxic T lymphocyte (CTL) responses in mediating AdV-induced protection is well understood, the involvement of CD4(+) T cell-provided signals in the development of functional CD8(+) CTL responses remain unclear. To explore CD4(+) T helper signals required for AdVova-stimulated CTL responses, we established an adoptive transfer system by transferring CD4(+) T cells derived from various knock out and transgenic mice into wild-type and/or CD4-deficient animals, followed by immunizing with recombinant ovalbumin (OVA)-expressing AdVova vector. Without CD4(+) T help, both primary and memory CTL responses were greatly reduced in this model, and were associated with increased PD-1 expression. The provision of OVA-specific CD4(+) T help in CD4(+) T cell-deficient mice restored AdVova-induced primary CTL responses, and supported survival and recall responses of AdVova-stimulated memory CTLs. These effects were specifically mediated by CD4(+) T cell-produced IL-2 and CD154 signals. Adoptive transfer of \"helped\" or \"unhelped\" effector and memory CTLs into naïve CD4(+) T cell-deficient or -sufficient mice also revealed an additional role for polyclonal CD4(+) T cell environment in the survival of AdVova-stimulated CTLs, partially explaining the extension of CTL contraction phase. Finally, during recall responses, CD4(+) T cell environment, particularly involving memory CD4(+) T cells, greatly enhanced expansion of memory CTLs. Collectively, our data strongly suggest a critical role for CD4(+) T help in multiple phases of AdV-stimulated CTL responses, and could partially explain certain failures in AdV-based immunization trials targeting malignant tumors and chronic diseases that are often associated with compromised CD4(+) T cell population and function.", "link"=>"http://www.mendeley.com/research/cd154-il2-signaling-cd4-t-cells-play-critical-role-multiple-phases-cd8-ctl-responses-following-adeno-1", "reader_count"=>13, "reader_count_by_academic_status"=>{"Researcher"=>1, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>1, "Other"=>1, "Student > Bachelor"=>2}, "reader_count_by_user_role"=>{"Researcher"=>1, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>1, "Other"=>1, "Student > Bachelor"=>2}, "reader_count_by_subject_area"=>{"Agricultural and Biological Sciences"=>6, "Medicine and Dentistry"=>3, "Immunology and Microbiology"=>4}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}}, "reader_count_by_country"=>{"Ireland"=>1, "Portugal"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/563982"], "description"=>"<p>(<b>a</b>) Ten days following immunization, total CD8<sup>+</sup> CTLs containing AdVova-specific effector CTLs were purified from B6.1 mice (CD45.1<sup>+</sup> background) and adoptively transferred to naïve congenic WT and MHCII<sup>−/−</sup> mice (CD45.2<sup>+</sup> background; ∼15×10<sup>6</sup>/mouse). The OVA-specific tetramer<sup>+</sup> CTLs were tracked after staining peripheral blood samples with tetramer reagent and congenic marker up to 30 days post-adoptive transfer. The values represent mean %±SD of OVA-specific tetramer<sup>+</sup> CTLs in total CD45.1<sup>+</sup> adoptively transferred T cell population at the indicated intervals (right panel) and are representative of two independent experiments with five to six mice per group. **<i>P</i><0.01, versus MHCII<sup>−/−</sup> mice. (<b>b</b>) Forty-five days after adoptive transfer, the above mice groups were challenged with BL6-10<sub>OVA.</sub> Twenty-four days after the challenge, both groups were assessed for tumor protection. Images represent distorted pathology of lungs, showing relative surface tumor burden. (<b>c</b>) Ninety days following the immunization, total CD8<sup>+</sup> T cells containing AdVova-specific memory CTLs were purified from WT mice and adoptively transferred into naïve WT and MHCII<sup>−/−</sup> mice (∼15×10<sup>6</sup>/mouse). The OVA-specific tetramer<sup>+</sup> CTLs were tracked in peripheral blood samples by tetramer staining. The values represent mean %±SD of OVA-specific tetramer<sup>+</sup> CTLs in total CD8<sup>+</sup> T cell population at the indicated intervals (right panel) and are representative of two independent experiments with four to six mice per group. **<i>P</i><0.01, versus MHCII<sup>−/−</sup> mice. (<b>d</b>) Thirty days after the adoptive transfer, the above mice groups (<b>c</b>) were challenged with BL6-10<sub>OVA</sub> and the relative surface tumor burden was assessed 24 days after the challenge as detailed above.</p>", "links"=>[], "tags"=>["cells", "advova", "transgene", "product-specific"], "article_id"=>234464, "categories"=>["Virology", "Microbiology", "Immunology"], "users"=>["Channakeshava Sokke Umeshappa", "Roopa Hebbandi Nanjundappa", "Yufeng Xie", "Andrew Freywald", "Yulin Deng", "Hong Ma", "Jim Xiang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047004.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Polyclonal_CD4_T_cells_support_maintenance_of_AdVova_transgene_product_specific_CTLs_/234464", "title"=>"Polyclonal CD4<sup>+</sup> T cells support maintenance of AdVova transgene product-specific CTLs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:11:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/563673"], "description"=>"<p>Following immunization, the AdVova-specific CTLs (<b>a</b>) and CD44<sup>+</sup>CD4<sup>+</sup> T cells (<b>b</b>) in the peripheral blood and/or spleens were analyzed by flow cytometry at the indicated time points after tetramer staining, and CD44 and CD4 double marker staining, respectively. The values in the figure (left panel) or line diagram (right panel) are presented as mean%±SD of OVA-specific CD8<sup>+</sup> CTLs in total CD8<sup>+</sup> T cell population (<b>a</b>) or of CD44<sup>+</sup> CD4<sup>+</sup> T cells in total CD4<sup>+</sup> T cell population (<b>b</b>), and are cumulative of three independent studies with three to five mice per group. (<b>c</b>) Following immunization, the spleen samples were analyzed for OVA-specific CD4<sup>+</sup> T cells by intracellular IFN-γ staining at the indicated intervals. The values (% frequencies) are cumulative of two independent experiments with three to four mice per group. *<i>P</i><0.05, versus matching controls.</p>", "links"=>[], "tags"=>["stimulates", "persistent"], "article_id"=>234157, "categories"=>["Virology", "Microbiology", "Immunology"], "users"=>["Channakeshava Sokke Umeshappa", "Roopa Hebbandi Nanjundappa", "Yufeng Xie", "Andrew Freywald", "Yulin Deng", "Hong Ma", "Jim Xiang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047004.g001", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_AdVova_stimulates_persistent_CD4_and_CD8_T_cell_responses_/234157", "title"=>"AdVova stimulates persistent CD4<sup>+</sup> and CD8<sup>+</sup> T cell responses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:10:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/564063"], "description"=>"<p>(<b>a</b>) A schematic protocol. After 90 days of immunization, total CD8<sup>+</sup> T cells containing memory CTLs were purified from WT B6 mice with helped CTLs or MHCII<sup>−/−</sup> mice with unhelped CTLs, adoptively transferred in equal numbers into the naïve secondary recipients, WT and MHCII<sup>−/−</sup> mice (∼15×10<sup>6</sup>/mouse), and assessed for recall potential after boosting. (<b>b</b>) Three days after adoptive transfer of helped or unhelped memory CTLs into naïve WT and MHCII<sup>−/−</sup> mice, all the mice groups were boosted with AdVova and monitored for the expansion of memory CTLs 6.5 days later. The values represent mean %±SD of OVA-specific tetramer<sup>+</sup> CTLs in total CD8<sup>+</sup> T cell population and are representative of two independent experiments with five to six mice per group. **<i>P</i><0.01, versus MHCII<sup>−/−</sup> mice with helped or unhelped memory CTLs.</p>", "links"=>[], "tags"=>["signals", "priming", "optimal"], "article_id"=>234554, "categories"=>["Virology", "Microbiology", "Immunology"], "users"=>["Channakeshava Sokke Umeshappa", "Roopa Hebbandi Nanjundappa", "Yufeng Xie", "Andrew Freywald", "Yulin Deng", "Hong Ma", "Jim Xiang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047004.g005", "stats"=>{"downloads"=>1, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CD4_T_cell_signals_provided_during_priming_and_recall_phase_are_required_for_optimal_secondary_responses_/234554", "title"=>"CD4<sup>+</sup> T cell signals provided during priming and recall phase are required for optimal secondary responses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:12:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/564150"], "description"=>"<p>(<b>a</b>) A schematic protocol. After 90 days following immunization, total CD8<sup>+</sup> T cells containing memory CTLs were purified from WT (helped memory CTLs) mice and adoptively transferred equally to the naïve secondary recipients, WT and MHCII<sup>−/−</sup> mice (∼15×10<sup>6</sup>/mouse). The MHCII<sup>−/−</sup> mice were additionally reconstituted with different types of CD4<sup>+</sup> T cells (∼15–20×10<sup>6</sup>/mouse) along with CD11c<sup>+</sup> DCs (∼0.5–1.0×10<sup>6</sup>/mouse). Both groups were boosted with AdVova and assessed for memory CTLs expansion. (<b>b</b>) Naïve B6.1/OTII CD4<sup>+</sup> T cells were co-cultured with irradiated BM DCova, as detailed in material and methods to generate Th1 cells. Th1 cells were then transferred to naïve congenic WT mice (∼10–15×10<sup>6</sup>/mouse). After 45 days, these cells were triple stained and phenotypically characterized for the expression of activation or memory markers (grey-shaded area) as shown in the figure. Irrelevant isotype-matched Abs were used as control (dotted thin lines). The value in the dot plot indicates % of OVA-specific CD4<sup>+</sup> T memory cells remaining in total CD4<sup>+</sup> T cell population. One representative of the two independent experiments is shown. (<b>c</b>) Naïve MHCII<sup>−/−</sup> mice were adoptively transferred with helped memory CTLs with naïve OTII T cells (∼1.5×10<sup>6</sup>/mouse), polyclonal CD4<sup>+</sup> T cells (∼15–20×10<sup>6</sup>/mouse) or polyclonal CD4<sup>+</sup> T cells containing OVA-specific memory CD4<sup>+</sup> T cells (∼15–20×10<sup>6</sup>/mouse) and CD11c<sup>+</sup> DCs (∼0.5–1.0×10<sup>6</sup>/mouse) as shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047004#pone-0047004-g006\" target=\"_blank\">Fig. 6a</a>. Three days later, all the groups were boosted with AdVova and the recall potential of the memory CTLs were assessed 6.5 days later. The values represent mean %±SD of OVA-specific tetramer<sup>+</sup> CTLs in total CD8<sup>+</sup> T cell population and are representative of two independent experiments with four to five mice per group. *<i>P</i><0.05 or **<i>P</i><0.01, versus MHCII<sup>−/−</sup> mice with helped memory CTLs alone.</p>", "links"=>[], "tags"=>["signals", "delivered", "priming", "optimal"], "article_id"=>234637, "categories"=>["Virology", "Microbiology", "Immunology"], "users"=>["Channakeshava Sokke Umeshappa", "Roopa Hebbandi Nanjundappa", "Yufeng Xie", "Andrew Freywald", "Yulin Deng", "Hong Ma", "Jim Xiang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047004.g006", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CD4_T_cell_signals_delivered_during_priming_and_recall_phase_are_required_for_optimal_secondary_responses_/234637", "title"=>"CD4<sup>+</sup> T cell signals delivered during priming and recall phase are required for optimal secondary responses.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:12:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/563850"], "description"=>"<p>(<b>a</b>) A schematic protocol. MHCII<sup>−/−</sup> or WT mice were adoptively transferred with monoclonal (∼1.5×10<sup>6</sup>/mouse) or polyclonal CD4<sup>+</sup> T cells (∼15–20×10<sup>6</sup>/mouse) with or without designated gene deficiency and supplied with spleen-derived CD11c<sup>+</sup> DCs (∼0.5–1.0×10<sup>6</sup>/mouse). One day later, both MHCII<sup>−/−</sup> and WT mice were i.v. immunized with AdVova followed by assessment of CTL proliferation in the peripheral blood at the indicated intervals. After 120 days (memory stage) following the immunization, all the groups were challenged with BL6-10<sub>OVA</sub> tumor cells and assessed for tumor protection. (<b>b</b>) Optimizing CD4<sup>+</sup> T cells dose required for CTL expansion in MHCII<sup>−/−</sup> mice. MHCII<sup>−/−</sup> mice were transferred with monoclonal (OTII) and/or polyclonal CD4<sup>+</sup> T cells and CD11c<sup>+</sup> DCs, as shown in the figure. One day later, all the groups were immunized and assessed for CTL proliferation by tetramer assay. The values represent mean %±SD of OVA-specific tetramer<sup>+</sup> CTLs in total CD8<sup>+</sup> T cell population and are representative of two independent experiments with three to four mice per group. **<i>P</i><0.01, versus MHCII<sup>−/−</sup> mice with no adoptive CD4<sup>+</sup> T cell transfer. (<b>c</b>) Molecular mechanisms of CD4<sup>+</sup> T cell help. MHCII<sup>−/−</sup> mice were transferred with polyclonal CD4<sup>+</sup> T cells with or without designated gene deficiency and CD11c<sup>+</sup> DCs as indicated. One day later, all the groups were immunized and subsequently assessed for CTL proliferation by tetramer assay. (<b>d</b>) Poor survival of adoptively transferred naïve CD4<sup>+</sup> T cells in MHCII<sup>−/−</sup> mice. Naïve CD4<sup>+</sup> T cells (∼15×10<sup>6</sup>/mouse) on CD45.1<sup>+</sup> background were transferred to congenic MHCII<sup>−/−</sup> mice (CD45.2<sup>+</sup>) and analyzed 3, 30 and 60 days later by flow cytometry. One representative figure of a group is shown in the dot plot. The values in dot plots represent mean±(SD)% of two independent experiments, each comprising two to three mice per group. (<b>e</b>) Molecular mechanisms of CD4<sup>+</sup> T cell help. MHCII<sup>−/−</sup> mice were transferred with monoclonal (OTII) CD4<sup>+</sup> T cells with or without designated gene deficiency and CD11c<sup>+</sup> DCs as indicated. One day later, all the groups were immunized and subsequently assessed for CTL proliferation by tetramer assay. In (<b>c</b>) and (<b>e</b>), the values represent mean %±SD of OVA-specific tetramer<sup>+</sup> CTLs in total CD8<sup>+</sup> T cell population on day 10 post-immunization (left panel) or at the indicated time points (right panel) and are representative of two independent experiments with five to six mice per group. **<i>P</i><0.01, versus MHCII<sup>−/−</sup> mice with no adoptive CD4<sup>+</sup> T cell transfer.</p>", "links"=>[], "tags"=>["molecular", "mechanisms", "ctl", "responses"], "article_id"=>234342, "categories"=>["Virology", "Microbiology", "Immunology"], "users"=>["Channakeshava Sokke Umeshappa", "Roopa Hebbandi Nanjundappa", "Yufeng Xie", "Andrew Freywald", "Yulin Deng", "Hong Ma", "Jim Xiang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047004.g003", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_molecular_mechanisms_of_CD4_T_cell_help_in_CTL_primary_responses_and_survival_/234342", "title"=>"The molecular mechanisms of CD4<sup>+</sup> T cell help in CTL primary responses and survival.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:11:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/563762"], "description"=>"<p>Following immunization, AdVova-specific CTLs were analyzed in the peripheral blood at different time points by tetramer (<b>a</b>) and intracellular IFN-γ (<b>b</b>) stainings. The values are presented as mean%±SD of OVA-specific tetramer<sup>+</sup> CTLs (<b>a</b>) or IFN-γ<sup>+</sup> CTLs (<b>b</b>) in total CD8<sup>+</sup> T cell population and are representative of two to three independent experiments with three to four mice per group. **<i>P</i><0.01, versus MHCII<sup>−/−</sup> mice. (<b>c</b>) Ten days following immunization, the proportions of CFSE<sup>high</sup>-OVAI-pulsed target cells lysed by effector CTLs were determined in the spleens by <i>in vivo</i> cytotoxicity assay. The values represent mean %±SD of targets remaining in spleens relative to controls and are representative of two independent experiments with three to four mice per group. (<b>d</b>) On day 75, following immunization, OVA-specific memory CTLs were characterized in spleen for PD-1 expression by flow cytometry. A representative figure from immunized groups along with matching isotype control is shown on the left. The values in the bar diagram represent the mean %±SD of PD-1<sup>+</sup> tetramer<sup>+</sup> CTLs in total tetramer<sup>+</sup> CTL population and are representative of two independent experiments with 3 to 4 mice per group. **<i>P</i><0.01, versus WT mice.</p>", "links"=>[], "tags"=>["cells", "kinetics", "adv", "transgene-specific", "ctl"], "article_id"=>234247, "categories"=>["Virology", "Microbiology", "Immunology"], "users"=>["Channakeshava Sokke Umeshappa", "Roopa Hebbandi Nanjundappa", "Yufeng Xie", "Andrew Freywald", "Yulin Deng", "Hong Ma", "Jim Xiang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047004.g002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CD4_T_cells_impact_the_kinetics_of_AdV_transgene_specific_CTL_populations_/234247", "title"=>"CD4<sup>+</sup> T cells impact the kinetics of AdV transgene-specific CTL populations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 22:10:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/564256"], "description"=>"a<p>One day prior to immunization, MHCII<sup>−/−</sup> mice were adoptively transferred with CD11c<sup>+</sup> DCs (∼0.5–1.0×10<sup>6</sup>/mouse) and naïve polyclonal (∼15–20×10<sup>6</sup>/mouse) or OTII CD4<sup>+</sup> T cells (∼1.5×10<sup>6</sup>/mouse) with or without designated gene deficiency, as indicated. 120 days later, all the immunized mice were challenged with BL6-10ova tumor cells. Twenty-four days after the challenge, lung tumor colonies were counted and graded. The data are cumulative of two independent experiments, each comprising five to six mice per group.</p>", "links"=>[], "tags"=>["mechanisms", "t-helper", "signals", "adv-specific", "ctl"], "article_id"=>234744, "categories"=>["Virology", "Microbiology", "Immunology"], "users"=>["Channakeshava Sokke Umeshappa", "Roopa Hebbandi Nanjundappa", "Yufeng Xie", "Andrew Freywald", "Yulin Deng", "Hong Ma", "Jim Xiang"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047004.t001", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Molecular_mechanisms_of_CD4_T_helper_signals_required_for_functional_AdV_specific_memory_CTL_responses_a_/234744", "title"=>"Molecular mechanisms of CD4<sup>+</sup> T-helper signals required for functional AdV-specific memory CTL responses<sup>a</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 22:13:18"}

PMC Usage Stats | Further Information

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Relative Metric

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