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Impact of Polymer-TLR-7/8 Agonist (Adjuvant) Morphology on the Potency and Mechanism of CD8 T Cell Induction
journal contribution
posted on 2019-01-04, 00:00 authored by Geoffrey
M. Lynn, Petr Chytil, Joseph R. Francica, Anna Lagová, Gray Kueberuwa, Andrew S. Ishizuka, Neeha Zaidi, Ramiro A. Ramirez-Valdez, Nicolas J. Blobel, Faezzah Baharom, Joseph Leal, Amy Q. Wang, Michael Y. Gerner, Tomáš Etrych, Karel Ulbrich, Leonard W. Seymour, Robert A. Seder, Richard LagaSmall
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.
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CCRimpact-8 agonistsmagnitude responsesvaccine adjuvantsIL -12CD 8 T cellshydrodynamicprotein antigenIFNmonocytesubmicrometer particleCD 8 T cell responsesfocus adjuvant activitytoxicitypolymer-TLRCD 8 T cell immunitylymph nodesTLR15 hvivonmlymph node cytokine productionlymphoid tissuespolymer compositionschain architecturemolecule Toll-like receptor -7CD 8 T Cell Induction
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