Impact of Polymer-TLR-7/8 Agonist (Adjuvant) Morphology on the Potency and Mechanism of CD8 T Cell Induction
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't
Grant support
17720
Cancer Research UK - United Kingdom
- MeSH
- Adjuvants, Immunologic administration & dosage chemistry pharmacology MeSH
- Lymphocyte Activation * MeSH
- Cell Line MeSH
- CD8-Positive T-Lymphocytes drug effects immunology MeSH
- Cytokines metabolism MeSH
- Hydrodynamics MeSH
- Cells, Cultured MeSH
- Micelles * MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Toll-Like Receptor 7 agonists MeSH
- Toll-Like Receptor 8 agonists MeSH
- Protein Binding MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Intramural MeSH
- Names of Substances
- Adjuvants, Immunologic MeSH
- Cytokines MeSH
- Micelles * MeSH
- Toll-Like Receptor 7 MeSH
- Toll-Like Receptor 8 MeSH
Small molecule Toll-like receptor-7 and -8 agonists (TLR-7/8a) can be used as vaccine adjuvants to induce CD8 T cell immunity but require formulations that prevent systemic toxicity and focus adjuvant activity in lymphoid tissues. Here, we covalently attached TLR-7/8a to polymers of varying composition, chain architecture and hydrodynamic behavior (∼300 nm submicrometer particles, ∼10 nm micelles and ∼4 nm flexible random coils) and evaluated how these parameters of polymer-TLR-7/8a conjugates impact adjuvant activity in vivo. Attachment of TLR-7/8a to any of the polymer compositions resulted in a nearly 10-fold reduction in systemic cytokines (toxicity). Moreover, both lymph node cytokine production and the magnitude of CD8 T cells induced against protein antigen increased with increasing polymer-TLR-7/8a hydrodynamic radius, with the submicrometer particle inducing the highest magnitude responses. Notably, CD8 T cell responses induced by polymer-TLR-7/8a were dependent on CCR2+ monocytes and IL-12, whereas responses by a small molecule TLR-7/8a that unexpectedly persisted in vaccine-site draining lymph nodes (T1/2 = 15 h) had less dependence on monocytes and IL-12 but required Type I IFNs. This study shows how modular properties of synthetic adjuvants can be chemically programmed to alter immunity in vivo through distinct immunological mechanisms.
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