Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Japan Agency for Medical Research and Development (AMED), Tokyo, Japan.
Division of Immunology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
J Allergy Clin Immunol. 2018 Jun;141(6):2156-2167.e9. doi: 10.1016/j.jaci.2017.11.048. Epub 2018 Feb 21.
Exposure to dietary constituents through the mucosal surface of the gastrointestinal tract generates oral tolerance that prevents deleterious T cell-mediated immunity. Although oral tolerance is an active process that involves emergence of CD4 forkhead box p3 (Foxp3) regulatory T (Treg) cells in gut-associated lymphoid tissues (GALTs) for suppression of effector T (Teff) cells, how antigen-presenting cells initiate this process remains unclear.
We sought to determine the role of plasmacytoid dendritic cells (pDCs), which are known as unconventional antigen-presenting cells, in establishment of oral tolerance.
GALT-associated pDCs in wild-type mice were examined for their ability to induce differentiation of CD4 Teff cells and CD4Foxp3 Treg cells in vitro. Wild-type and pDC-ablated mice were fed oral antigen to compare their intestinal generation of CD4Foxp3 Treg cells and induction of oral tolerance to protect against Teff cell-mediated allergic inflammation.
GALT-associated pDCs preferentially generate CD4Foxp3 Treg cells rather than CD4 Teff cells, and such generation requires an autocrine loop of TGF-β for its robust production. A deficiency of pDCs abrogates antigen-specific de novo generation of CD4Foxp3 Treg cells occurring in GALT after antigenic feeding. Furthermore, the absence of pDCs impairs development of oral tolerance, which ameliorates the progression of delayed-type hypersensitivity and systemic anaphylaxis, as well as allergic asthma, accompanied by an enhanced antigen-specific CD4 Teff cell response and antibody production.
pDCs are required for establishing oral tolerance to prevent undesirable allergic responses, and they might serve a key role in maintaining gastrointestinal immune homeostasis.
通过胃肠道黏膜表面接触膳食成分可产生防止有害 T 细胞介导免疫的口服耐受。虽然口服耐受是一个涉及到在肠道相关淋巴组织（GALTs）中出现 CD4 叉头框 p3（Foxp3）调节性 T（Treg）细胞以抑制效应 T（Teff）细胞的主动过程，但抗原呈递细胞如何启动该过程尚不清楚。
我们旨在确定浆细胞样树突状细胞（pDCs）在建立口服耐受中的作用，pDCs 是已知的非传统抗原呈递细胞。
在野生型小鼠中检查 GALT 相关的 pDCs 体外诱导 CD4 Teff 细胞和 CD4Foxp3 Treg 细胞分化的能力。用口服抗原喂养野生型和 pDC 缺失型小鼠，比较它们肠道中 CD4Foxp3 Treg 细胞的产生和诱导口服耐受以防止 Teff 细胞介导的过敏炎症。
GALT 相关的 pDCs 优先产生 CD4Foxp3 Treg 细胞而不是 CD4 Teff 细胞，这种产生需要 TGF-β 的自分泌环来进行其强烈的产生。pDC 缺失会破坏抗原喂养后 GALT 中发生的抗原特异性 CD4Foxp3 Treg 细胞的从头生成。此外，pDC 的缺失会损害口服耐受的发展，从而改善迟发型超敏反应和全身性过敏反应以及过敏性哮喘的进展，同时增强抗原特异性 CD4 Teff 细胞的反应和抗体产生。
pDCs 是建立口服耐受以防止不良过敏反应所必需的，它们可能在维持胃肠道免疫稳态方面发挥关键作用。
