Division of Periodontology, Department of Developmental and Surgical Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, United States.
Front Immunol. 2020 Apr 23;11:677. doi: 10.3389/fimmu.2020.00677. eCollection 2020.
In periodontitis contributes to the development of a dysbiotic oral microbiome. This altered ecosystem elicits a diverse innate and adaptive immune response that simultaneously involves Th1, Th17, and Treg cells. It has been shown that Th17 cells can alter their gene expression to produce interferon-gamma (IFN-γ). Forkhead box P3 (Foxp3) is considered the master regulator of Treg cells that produce inhibitory cytokines like IL-10. Differentiation pathways that lead to Th17 and Treg cells from naïve progenitors are considered antagonistic. However, it has been reported that Treg cells expressing IL-17A as well as IFN-γ producing Th17 cells have been observed in several inflammatory conditions. Each scenario appears plausible with T cell transdifferentiation resulting from persistent microbial challenge and consequent inflammation. We established that oral colonization with drives an initial IL-17A dominated Th17 response in the oral mucosa that is dependent on intraepithelial Langerhans cells (LCs). We hypothesized that Treg cells contribute to this initial IL-17A response through transient expression of IL-17A and that persistent mucosal colonization with drives Th17 cells toward an IFN-γ phenotype at later stages of infection. We utilized fate-tracking mice where IL-17A- or Foxp3-promoter activity drives the permanent expression of red fluorescent protein tdTomato to test our hypothesis. At day 28 of infection timeline, Th17 cells dominated in the oral mucosa, outnumbering Th1 cells by 3:1. By day 48 this dominance was inverted with Th1 cells outnumbering Th17 cells by nearly 2:1. Tracking tdTomato Th17 cells revealed only sporadic transdifferentiation to an IFN-γ-producing phenotype by day 48; the appearance of Th1 cells at day 48 was due to a late Th1 response. tdTomato Foxp3 T cells were 35% of the total live CD4T cells in the oral mucosa and 3.9% of them developed a transient IL-17A-producing phenotype by day 28. Interestingly, by day 48 these IL-17A-producing Foxp3 T cells had disappeared. Therefore, persistent oral infection stimulates an initial IL-17A-biased response led by Th17 cells and a small but significant number of IL-17A-expressing Treg cells that changes into a late Th1 response with only sporadic transdifferentiation of Th17 cells.
在牙周炎中， 有助于形成一种失调的口腔微生物组。这种改变的生态系统引发了多样化的先天和适应性免疫反应，同时涉及 Th1、Th17 和 Treg 细胞。已经表明，Th17 细胞可以改变其基因表达以产生干扰素-γ (IFN-γ)。叉头框 P3 (Foxp3) 被认为是 Treg 细胞的主要调节因子，Treg 细胞产生抑制性细胞因子，如 IL-10。从幼稚前体分化为 Th17 和 Treg 细胞的途径被认为是拮抗的。然而，据报道，在几种炎症情况下已经观察到表达 IL-17A 的 Treg 细胞以及产生 IFN-γ的 Th17 细胞。在持续的微生物挑战和随之而来的炎症导致 T 细胞转分化的情况下，每种情况似乎都是合理的。我们已经确定， 口腔定植导致口腔黏膜中最初以 IL-17A 为主导的 Th17 反应，这依赖于上皮内朗格汉斯细胞 (LCs)。我们假设 Treg 细胞通过瞬时表达 IL-17A 有助于这种最初的 IL-17A 反应，并且 持续的黏膜定植导致 Th17 细胞在感染后期向 IFN-γ表型发展。我们利用 IL-17A 或 Foxp3 启动子活性驱动红色荧光蛋白 tdTomato 永久表达的命运追踪小鼠来检验我们的假设。在感染时间线的第 28 天，Th17 细胞在口腔黏膜中占主导地位，数量是 Th1 细胞的 3:1。到第 48 天，这种优势被逆转，Th1 细胞的数量几乎是 Th17 细胞的两倍。追踪 tdTomato Th17 细胞显示，到第 48 天只有零星的向产生 IFN-γ 的表型转化；第 48 天出现的 Th1 细胞是由于晚期 Th1 反应。口腔黏膜中活的 CD4T 细胞中，tdTomato Foxp3 T 细胞占 35%，其中 3.9%在第 28 天出现短暂的 IL-17A 产生表型。有趣的是，到第 48 天，这些产生 IL-17A 的 Foxp3 T 细胞已经消失。因此，持续的口腔 感染刺激最初以 Th17 细胞为主导的 IL-17A 偏向性反应，以及一小部分但数量显著的表达 IL-17A 的 Treg 细胞，这些细胞在 Th17 细胞的偶发转分化下转变为晚期 Th1 反应。
