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

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 Laga

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)854-870
Number of pages17
Issue number2
StatePublished - Feb 11 2019
Externally publishedYes

ASJC Scopus subject areas

  • Bioengineering
  • Biomaterials
  • Polymers and Plastics
  • Materials Chemistry


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