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

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
Biomacromolecules 2019 v.20 no.2 pp. 854-870
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
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.