Cited by 53Immunotherapy and Immune ResponsesT-cell and B-cell ImmunologyImmune responses and vaccinations

Combined triggering of dendritic cell receptors results in synergistic activation and potent cytotoxic immunity

Wells, James W, Cowled, Christopher J, Farzaneh, Farzin, Noble, Alistair·2008·The Journal of Immunology

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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Crossref · 10.4049/jimmunol.181.5.3422

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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
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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