Impact of polymer-TLR-7/8 agonist (adjuvant) morphology on the potency and mechanism of CD8 T cell induction

0501308 - ÚMCH 2020 RIV US eng J - Journal Article
Lynn, G. M. - Chytil, Petr - Francica, J. R. - Lagová, A. - Kueberuwa, G. - Ishizuka, A. S. - Zaidi, N. - Ramirez-Valdez, R. A. - Blobel, N. J. - Baharom, F. - Leal, J. - Wang, A. Q. - Gerner, M. Y. - Etrych, Tomáš - Ulbrich, Karel - Seymour, L. W. - Seder, R. A. - Laga, Richard
Impact of polymer-TLR-7/8 agonist (adjuvant) morphology on the potency and mechanism of CD8 T cell induction.
Biomacromolecules. Roč. 20, č. 2 (2019), s. 854-870. ISSN 1525-7797. E-ISSN 1526-4602
R&D Projects: GA ČR(CZ) GJ16-14957Y; GA MŠMT(CZ) LQ1604
Institutional support: RVO:61389013
Keywords : hydrophilic polymers * toll-like receptor-7/8 agonists * polymer immunostimulants
OECD category: Polymer science
Impact factor: 6.092, year: 2019
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acs.biomac.8b01473

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.
Permanent Link: http://hdl.handle.net/11104/0293622