Bedford James G, Heinlein Melanie, Garnham Alexandra L, Nguyen Thi H O, Loudovaris Tom, Ge Chenghao, Mannering Stuart I, Elliott Michael, Tangye Stuart G, Kedzierska Katherine, Gray Daniel H D, Heath William R, Wakim Linda M
Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Sci Immunol. 2020 Oct 9;5(52). doi: 10.1126/sciimmunol.abb5439.
The nasal-associated lymphoid tissues (NALTs) are mucosal-associated lymphoid organs embedded in the submucosa of the nasal passage. NALTs represent a known site for the deposition of inhaled antigens, but little is known of the mechanisms involved in the induction of immunity within this lymphoid tissue. We find that during the steady state, conventional dendritic cells (cDCs) within the NALTs suppress T cell responses. These cDCs, which are also prevalent within human NALTs (tonsils/adenoids), express a unique transcriptional profile and inhibit T cell proliferation via contact-independent mechanisms that can be diminished by blocking the actions of reactive oxygen species and prostaglandin E Although the prevention of unrestrained immune activation to inhaled antigens appears to be the default function of NALT cDCs, inflammation after localized virus infection recruited monocyte-derived DCs (moDCs) to this region, which diluted out the suppressive DC pool, and permitted local T cell priming. Accommodating for inflammation-induced temporal changes in NALT DC composition and function, we developed an intranasal vaccine delivery system that coupled the recruitment of moDCs with the sustained release of antigen into the NALTs, and we were able to substantially improve T cell responses after intranasal immunization. Thus, homeostasis and immunity to inhaled antigens is tuned by inflammatory signals that regulate the balance between conventional and moDC populations within the NALTs.
鼻相关淋巴组织（NALTs）是嵌入鼻道黏膜下层的黏膜相关淋巴器官。NALTs是吸入抗原沉积的已知部位，但对于该淋巴组织内免疫诱导所涉及的机制知之甚少。我们发现，在稳态期间，NALTs内的传统树突状细胞（cDCs）会抑制T细胞反应。这些在人类NALTs（扁桃体/腺样体）中也普遍存在的cDCs，表达独特的转录谱，并通过不依赖接触的机制抑制T细胞增殖，这种机制可通过阻断活性氧和前列腺素E的作用而减弱。尽管防止对吸入抗原的无节制免疫激活似乎是NALT cDCs的默认功能，但局部病毒感染后的炎症会将单核细胞衍生的DCs（moDCs）募集到该区域，这稀释了抑制性DC池，并允许局部T细胞启动。为适应炎症诱导的NALT DC组成和功能的时间变化，我们开发了一种鼻内疫苗递送系统，该系统将moDCs的募集与抗原在NALTs中的持续释放相结合，并且我们能够在鼻内免疫后显著改善T细胞反应。因此，对吸入抗原的稳态和免疫是由调节NALTs内传统DC和moDC群体之间平衡的炎症信号所调节的。
