Title | Impact of Polymer-TLR-7/8 Agonist (Adjuvant) Morphology on the Potency and Mechanism of CD8 T Cell Induction. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Lynn GM, Chytil P, Francica JR, Lagová A, Kueberuwa G, Ishizuka AS, Zaidi N, Ramirez-Valdez RA, Blobel NJ, Baharom F, Leal J, Wang AQ, Gerner MY, Etrych T, Ulbrich K, Seymour LW, Seder RA, Laga R |
Journal | Biomacromolecules |
Volume | 20 |
Issue | 2 |
Pagination | 854-870 |
Date Published | 2019 02 11 |
ISSN | 1526-4602 |
Abstract | 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. |
DOI | 10.1021/acs.biomac.8b01473 |
Alternate Journal | Biomacromolecules |
PubMed ID | 30608149 |
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