Impact of Polymer-TLR-7/8 Agonist (Adjuvant) Morphology on the Potency and Mechanism of CD8 T Cell Induction
作者: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
DOI:10.1021/acs.biomac.8b01473
日期:2019.2.11
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.
小分子Toll样受体-7和-8激动剂(TLR-7/8a)可以作为疫苗佐剂用于诱导CD8 T细胞免疫,但需要特定的配方以防止全身毒性,并将佐剂活性集中在淋巴组织中。在此,我们将TLR-7/8a共价结合到不同组成、链结构和流体动力学行为的聚合物上(约300 nm亚微米粒子、约10 nm胶束和约4 nm的柔性随机卷曲),并评估这些聚合物-TLR-7/8a结合物的参数如何影响其在体内的佐剂活性。将TLR-7/8a连接到任何聚合物组成上,系统性细胞因子(毒性)几乎减少了10倍。此外,淋巴结细胞因子产生和针对蛋白抗原诱导的CD8 T细胞的强度随着聚合物-TLR-7/8a的流体动力学半径增加而增加,亚微米粒子诱导的响应强度最高。值得注意的是,聚合物-TLR-7/8a诱导的CD8 T细胞反应依赖于CCR2+单核细胞和IL-12,而小分子TLR-7/8a的反应(意外地在疫苗接种部位引流的淋巴结中持续存在,半衰期为15小时)对单核细胞和IL-12的依赖性较小,但需要I型干扰素。这项研究展示了合成佐剂的模块化特性如何通过不同的免疫机制进行化学编程,以改变体内的免疫反应。