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Impact of Polymer-TLR-7/8 Agonist (Adjuvant) Morphology on the Potency and Mechanism of CD8 T Cell Induction

Author:
Lynn, Geoffrey M., Chytil, Petr, Francica, Joseph R., Lagová, Anna, Kueberuwa, Gray, Ishizuka, Andrew S., Zaidi, Neeha, Ramirez-Valdez, Ramiro A., Blobel, Nicolas J., Baharom, Faezzah, Leal, Joseph, Wang, Amy Q., Gerner, Michael Y., Etrych, Tomáš, Ulbrich, Karel, Seymour, Leonard W., Seder, Robert A., Laga, Richard
Source:
Biomacromolecules 2019 v.20 no.2 pp. 854-870
ISSN:
1526-4602
Subject:
CD8-positive T-lymphocytes, Toll-like receptor 7, agonists, antigens, chemical bonding, hydrodynamics, immunity, interleukin-12, lymph nodes, micelles, monocytes, polymers, tissues, toxicity, vaccine adjuvants
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.
Agid:
6305769