A universal influenza vaccine must provide protection against antigenically divergent influenza viruses either through broadly neutralizing antibodies or cross-reactive T cells. Here, intranasal immunizations with recombinant adenoviral vectors (rAd) encoding hemagglutinin (HA) and nucleoprotein (NP) in combination with rAd-Interleukin-(IL)-1β or rAd-IL-18 were evaluated for their efficacy in BALB/c mice. Mucosal delivery of rAd-IL-1β enhanced HA-specific antibody responses including strain-specific neutralizing antibodies. Nevertheless, the beneficial effects on the local T cell responses were much more impressive reflected by increased numbers of CD103⁺CD69⁺ tissue-resident memory T cells (T_RM). This increased immunogenicity translated into superior protection against infections with homologous and heterologous strains including H1N1, pH1N1, H3N2, and H7N7. Inhibition of the egress of circulating T cells out of the lymph nodes during the heterologous infection had no impact on the degree of protection underscoring the unique potential of T_RM for the local containment of mucosal infections. The local co-expression of IL-1β and antigen lead to the activation of critical checkpoints in the formation of T_RM including activation of epithelial cells, expression of chemokines and adhesion molecules, recruitment of lung-derived CD103⁺ DCs, and finally local T_RM imprinting. Given the importance of T_RM-mediated protection at mucosal barriers, this study has major implications for vaccine development.

中文翻译：

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IL-1β作为粘膜疫苗佐剂：组织驻留记忆T细胞的特异性诱导提高了对甲型流感病毒的异亚型免疫。

通用流感疫苗必须通过广泛中和抗体或交叉反应性 T 细胞提供针对抗原性不同流感病毒的保护。在这里，使用编码血凝素 (HA) 和核蛋白 (NP) 的重组腺病毒载体 (rAd) 与 rAd-白介素-(IL)-1β 或 rAd-IL-18 组合进行鼻内免疫，评估了它们在 BALB/c 小鼠中的功效。rAd-IL-1β 的粘膜递送增强了 HA 特异性抗体反应，包括菌株特异性中和抗体。^{然而，CD103 +} CD69 ⁺组织驻留记忆 T 细胞 (TR _RM ) 数量的增加反映了对局部 T 细胞反应的有益影响。). 这种增加的免疫原性转化为对同源和异源毒株（包括 H1N1、pH1N1、H3N2 和 H7N7）感染的卓越保护。在异源感染期间抑制循环 T 细胞流出淋巴结对保护程度没有影响，这强调了 T _RM在局部遏制粘膜感染方面的独特潜力。IL-1β 和抗原的局部共表达导致 TRM 形成中关键检查点的激活，包括上皮细胞的激活、趋化因子和粘附分子的表达、肺源性 CD103 + DC 的募集_，^以及最终的局部 T _RM压印。鉴于 T _{RM的重要性}-介导的粘膜屏障保护，这项研究对疫苗开发具有重要意义。