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

Publication Type	Academic Article
Authors	Lynn G, Chytil P, Francica J, Lagová A, Kueberuwa G, Ishizuka A, Zaidi N, Ramirez-Valdez R, Blobel N, Baharom F, Leal J, Wang A, Gerner M, Etrych T, Ulbrich K, Seymour L, Seder R, Laga R
Journal	Biomacromolecules
Volume	20
Issue	2
Pagination	854-870
Date Published	01/22/2019
ISSN	1526-4602
Keywords	Adjuvants, Immunologic, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Micelles, Toll-Like Receptor 7, Toll-Like Receptor 8
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
PubMed ID	30608149