Combined triggering of dendritic cell receptors results in synergistic activation and potent cytotoxic immunity
Abstract
Elimination of malignant cells and intracellular infections involves collaboration between CTLs and Th1 inflammation. Dendritic cells drive this response via costimulation and cytokines. We have defined key signals required for the exponential expansion of specific CD8(+) T cells in vivo in mice. Immunization with two or more TLR agonists, anti-CD40, IFN-gamma, and surfactant were sufficient to drive unprecedented levels of CD8 response to peptide or protein Ag and highly polarized Th1 CD4 responses. CD40 signaling was required for CD8 expansion but could be provided by a concomitant CD4 Th response in place of anti-CD40. Triggering of these pathways activated migration and activation of myeloid and plasmacytoid dendritic cells and secretion of IL-12. Cross-presentation can thus be exploited to induce potent cytotoxic responses and long-term memory to peptide/protein Ags. When combined with a tumor-associated peptide from tyrosinase-related protein 2, our combined adjuvant approach effectively halted tumor growth in an in vivo melanoma model and was more effective than anti-CD40 and a single TLR agonist. Antitumor immunity was associated with long-lived effector memory CD8 cells specific for the naturally processed and presented tumor Ag, and tumor protection was partially but not entirely dependent on CD8 T cells. This flexible strategy is more effective than existing adjuvants and provides a technological platform for rapid vaccine development.
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Complete Freund adjuvant can only be used in animals because it can cause damaging skin inflammation.
“The most effective is generally considered complete Freund adjuvant, which can only be used in animals because it can cause a damaging skin inflammation (213).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [213]
CASAC formulation results in potent cytotoxic T cell-mediated immunity in young mice.
“This formulation results in potent cytotoxic T cell-mediated immunity in young mice.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [213]
Complete Freund adjuvant is generally considered the most effective adjuvant.
“The most effective is generally considered complete Freund adjuvant, which can only be used in animals because it can cause a damaging skin inflammation (213).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [213]
CASAC strategy is more effective than existing adjuvants.
“This strategy is more effective than existing adjuvants and provides a technological platform for rapid vaccine development (213).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [213]
CASAC stimulation activates both mDCs and pDCs with IL-12 secretion.
“CASAC stimulation activates both mDCs and pDCs with IL-12 secretion.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [213]
Immunization with two or more TLR agonists, an activator anti-CD40 antibody, IFN-γ, and surfactants was sufficient to drive unprecedented levels of CD8 responses to peptides or protein antigens.
“In fact, immunization with two or more TLR agonists, an activator anti-CD40 antibody, IFN-γ, and surfactants were sufficient to drive unprecedented levels of CD8 responses to peptides or protein antigens and highly polarized Th1 CD4 responses.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [213]
CASAC provides a technological platform for rapid vaccine development.
“This strategy is more effective than existing adjuvants and provides a technological platform for rapid vaccine development (213).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [213]
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Aiello, A., Farzaneh, F., Candore, G., Caruso, C., Davinelli, S., Gambino, C. M., Ligotti, M. E., Zareian, N., & Accardi, G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02247 · Cited by 693 · see citing works
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Self-citation
- Authors
- Wells, J. W., Cowled, C. J., Farzaneh, F., & Noble, A.
- Affiliations
- Guy's Hospital (GB)
- King's College London (GB)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-09-01
- Volume
- 181
- Issue
- 5
- Pages
- 3422-3431
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1537832481
- Cited by
- 53
- References
- 51
- Citations by year
- 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 2 · 2015: 8 · 2014: 1 · 2013: 2 · 2012: 9
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- TLR agonists, anti-CD40 antibody, interferon-gamma, surfactants, CD8+ T cell proliferation, Th1 response, cross-presentation, IL-12, plasmacytoid dendritic cells, myeloid dendritic cells, melanoma vaccine, tyrosinase-related protein 2, tumor-associated peptides, memory CD8+ T cells, antitumor immunity, adjuvants
- MeSH terms
- Animals, Antibodies, Antigens, Neoplasm, Cytotoxicity, Immunologic, Dendritic Cells, Drug Synergism, Lymphocyte Activation, Melanoma, Experimental, Receptors, Immunologic, CD8-Positive T-Lymphocytes, Th1 Cells, CD40 Antigens, Cancer Vaccines, Intramolecular Oxidoreductases, Cross-Priming, Cell Proliferation, Toll-Like Receptors, Mice
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