Mary H. Weiser Food Allergy Center, Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, MI, United States.
Front Immunol. 2019 May 8;10:916. doi: 10.3389/fimmu.2019.00916. eCollection 2019.
Mucosal surfaces are the primary point of entry for many infectious agents and mucosal immune responses serve as the primary defense to these pathogens. In order to mount an effective mucosal immune response, it is important to induce T cell homing to mucosal surfaces. Conventional vaccine adjuvants induce strong systemic immunity but often fail to produce mucosal immunity. We have developed an oil-in-water nanoemulsion (NE) adjuvant that provides mucosal immunity and efficient protection against mucosal pathogens when administered as part of an intranasal vaccine. In the present study, we demonstrate that intranasal immunization with NE indirectly activates the retinaldehyde dehydrogenase (RALDH) activity in dendritic cells through epithelial cell activity leading to SIgA as well as potent cellular responses and expression of α4β7 and CCR9 gut homing receptors on T cells. Confirming these findings, stimulation of splenocytes from NE nasally immunized animals showed increase in Th1/Th17 cytokines while suppressing Th2 responses. In examining mechanisms underlying this activation NE activated RALDH via MyD88 dependent pathways in DCs but did not activate the retinoic acid receptor directly. These results suggest that RALDH immune activities can be achieved by epithelial activation without direct RAR activation, which has significant implications for understanding mucosal immunity and the design of mucosal vaccines.
黏膜表面是许多传染性病原体的主要进入点，黏膜免疫反应是抵御这些病原体的主要防御机制。为了产生有效的黏膜免疫反应，诱导 T 细胞归巢到黏膜表面是很重要的。传统的疫苗佐剂能诱导强烈的全身免疫反应，但往往不能产生黏膜免疫反应。我们开发了一种油包水纳米乳（NE）佐剂，当作为鼻内疫苗的一部分使用时，它能提供黏膜免疫和对黏膜病原体的有效保护。在本研究中，我们证明了通过上皮细胞的活性，鼻内免疫 NE 可间接激活树突状细胞中的视黄醛脱氢酶（RALDH）活性，从而导致 SIgA 以及有效的细胞反应和 T 细胞上α4β7 和 CCR9 肠道归巢受体的表达。证实了这些发现，刺激经 NE 鼻内免疫的动物的脾细胞显示 Th1/Th17 细胞因子增加，同时抑制 Th2 反应。在研究这种激活的机制时，NE 通过 DC 中的 MyD88 依赖性途径激活了 RALDH，但没有直接激活 RAR。这些结果表明，RALDH 的免疫活性可以通过上皮细胞的激活而不通过直接的 RAR 激活来实现，这对理解黏膜免疫和黏膜疫苗的设计具有重要意义。
