CpG-ODN Facilitates Effective Intratracheal Immunization and Recall of Memory against Neoantigen-Expressing Alveolar Cells
Intrapulmonary immune reactions are impaired by the tolerogenic environment of the lung. This is manifested by the absence of effective endogenous T cell responses upon neoantigen expression. This tolerance is considered to contribute to lung cancer and inefficient immune therapeutic interventions....
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01201/full |
| _version_ | 1818959023133687808 |
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| author | Mathias Riehn Marcin Cebula Hansjörg Hauser Dagmar Wirth Dagmar Wirth |
| author_facet | Mathias Riehn Marcin Cebula Hansjörg Hauser Dagmar Wirth Dagmar Wirth |
| author_sort | Mathias Riehn |
| collection | DOAJ |
| description | Intrapulmonary immune reactions are impaired by the tolerogenic environment of the lung. This is manifested by the absence of effective endogenous T cell responses upon neoantigen expression. This tolerance is considered to contribute to lung cancer and inefficient immune therapeutic interventions. To investigate the mechanisms contributing to lung tolerance and to overcome these restrictions, we developed a transgenic mouse model with induction of a neoantigen (OVA) exclusively in alveolar type II epithelial cells. This model is characterized by the absence of functional endogenous T cell responses upon OVA neoantigen induction. Standard DNA and protein vaccination protocols resulted in the accumulation of high numbers of antigen-specific CD8 T cells in the lung. However, clearance of antigen-expressing cells was not achieved. To overcome this tolerance, we induced inflammatory conditions by coapplication of the TLR ligands LPS and CpG-ODN during intrapulmonary vaccinations. Both ligands induced high numbers of neoantigen-specific T cells in the lung. However, only coapplication of CpG-ODN was sufficient to establish functional cytotoxic responses resulting in the elimination of neoantigen presenting target cells. Remarkably, CpG-ODN was also crucial for functional memory responses upon re-induction of the neoantigen. The results highlight the need of TLR9 co-stimulation for overcoming tolerization, which might be a key factor for therapeutic interventions. |
| first_indexed | 2024-12-20T11:35:02Z |
| format | Article |
| id | doaj.art-c0b6f9e702b0470b9c3e5ec37e7a3fd8 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T11:35:02Z |
| publishDate | 2017-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c0b6f9e702b0470b9c3e5ec37e7a3fd82022-12-21T19:42:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-09-01810.3389/fimmu.2017.01201290167CpG-ODN Facilitates Effective Intratracheal Immunization and Recall of Memory against Neoantigen-Expressing Alveolar CellsMathias Riehn0Marcin Cebula1Hansjörg Hauser2Dagmar Wirth3Dagmar Wirth4Research Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, GermanyResearch Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, GermanyResearch Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, GermanyResearch Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, GermanyDivision of Experimental Hematology, Hannover Medical School, Hannover, GermanyIntrapulmonary immune reactions are impaired by the tolerogenic environment of the lung. This is manifested by the absence of effective endogenous T cell responses upon neoantigen expression. This tolerance is considered to contribute to lung cancer and inefficient immune therapeutic interventions. To investigate the mechanisms contributing to lung tolerance and to overcome these restrictions, we developed a transgenic mouse model with induction of a neoantigen (OVA) exclusively in alveolar type II epithelial cells. This model is characterized by the absence of functional endogenous T cell responses upon OVA neoantigen induction. Standard DNA and protein vaccination protocols resulted in the accumulation of high numbers of antigen-specific CD8 T cells in the lung. However, clearance of antigen-expressing cells was not achieved. To overcome this tolerance, we induced inflammatory conditions by coapplication of the TLR ligands LPS and CpG-ODN during intrapulmonary vaccinations. Both ligands induced high numbers of neoantigen-specific T cells in the lung. However, only coapplication of CpG-ODN was sufficient to establish functional cytotoxic responses resulting in the elimination of neoantigen presenting target cells. Remarkably, CpG-ODN was also crucial for functional memory responses upon re-induction of the neoantigen. The results highlight the need of TLR9 co-stimulation for overcoming tolerization, which might be a key factor for therapeutic interventions.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01201/fullneoantigencytotoxic T cellstolerogenicalveolar tractimmune modulation |
| spellingShingle | Mathias Riehn Marcin Cebula Hansjörg Hauser Dagmar Wirth Dagmar Wirth CpG-ODN Facilitates Effective Intratracheal Immunization and Recall of Memory against Neoantigen-Expressing Alveolar Cells Frontiers in Immunology neoantigen cytotoxic T cells tolerogenic alveolar tract immune modulation |
| title | CpG-ODN Facilitates Effective Intratracheal Immunization and Recall of Memory against Neoantigen-Expressing Alveolar Cells |
| title_full | CpG-ODN Facilitates Effective Intratracheal Immunization and Recall of Memory against Neoantigen-Expressing Alveolar Cells |
| title_fullStr | CpG-ODN Facilitates Effective Intratracheal Immunization and Recall of Memory against Neoantigen-Expressing Alveolar Cells |
| title_full_unstemmed | CpG-ODN Facilitates Effective Intratracheal Immunization and Recall of Memory against Neoantigen-Expressing Alveolar Cells |
| title_short | CpG-ODN Facilitates Effective Intratracheal Immunization and Recall of Memory against Neoantigen-Expressing Alveolar Cells |
| title_sort | cpg odn facilitates effective intratracheal immunization and recall of memory against neoantigen expressing alveolar cells |
| topic | neoantigen cytotoxic T cells tolerogenic alveolar tract immune modulation |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01201/full |
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