Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111, USA.
J Immunol. 2012 Sep 1;189(5):2512-20. doi: 10.4049/jimmunol.1102892. Epub 2012 Jul 27.
Immunological diseases such as inflammatory bowel disease (IBD) are infrequent in less developed countries, possibly because helminths provide protection by modulating host immunity. In IBD murine models, the helminth Heligmosomoides polygyrus bakeri prevents colitis. It was determined whether H. polygyrus bakeri mediated IBD protection by altering dendritic cell (DC) function. We used a Rag IBD model where animals were reconstituted with IL10⁻/⁻ T cells, making them susceptible to IBD and with OVA Ag-responsive OT2 T cells, allowing study of a gut antigenic response. Intestinal DC from H. polygyrus bakeri-infected Rag mice added to lamina propria mononuclear cells (LPMC) isolated from colitic animals blocked OVA IFN-γ/IL-17 responses in vitro through direct contact with the inflammatory LPMC. DC from uninfected Rag mice displayed no regulatory activity. Transfer of DC from H. polygyrus bakeri-infected mice into Rag mice reconstituted with IL10⁻/⁻ T cells protected animals from IBD, and LPMC from these mice lost OVA responsiveness. After DC transfer, OT2 T cells populated the intestines normally. However, the OT2 T cells were rendered Ag nonresponsive through regulatory action of LPMC non-T cells. The process of regulation appeared to be regulatory T cell independent. Thus, H. polygyrus bakeri modulates intestinal DC function, rendering them tolerogenic. This appears to be an important mechanism through which H. polygyrus bakeri suppresses colitis. IFN-γ and IL-17 are colitogenic. The capacity of these DC to block a gut Ag-specific IFN-γ/IL-17 T cell response also is significant.
免疫性疾病，如炎症性肠病（IBD）在欠发达国家很少见，这可能是因为寄生虫通过调节宿主免疫来提供保护。在 IBD 鼠模型中，寄生虫 Heligmosomoides polygyrus bakeri 可预防结肠炎。本研究旨在确定 H. polygyrus bakeri 是否通过改变树突状细胞（DC）功能来介导 IBD 保护。我们使用 Rag IBD 模型，其中动物用 IL10⁻/⁻ T 细胞重建，使它们易患 IBD，并具有 OVA Ag 反应性 OT2 T 细胞，从而可以研究肠道抗原反应。从感染 H. polygyrus bakeri 的 Rag 鼠的肠道 DC 添加到来自结肠炎动物的固有层单核细胞（LPMC）中，通过与炎症性 LPMC 的直接接触，在体外阻断 OVA IFN-γ/IL-17 反应。来自未感染 Rag 鼠的 DC 没有显示出调节活性。将来自 H. polygyrus bakeri 感染鼠的 DC 转移到用 IL10⁻/⁻ T 细胞重建的 Rag 鼠中，可以保护动物免受 IBD 的侵害，并且这些鼠的 LPMC 失去了对 OVA 的反应性。在 DC 转移后，OT2 T 细胞正常定植于肠道。然而，通过 LPMC 非 T 细胞的调节作用，OT2 T 细胞变得对 Ag 无反应性。该调节过程似乎不依赖于调节性 T 细胞。因此，H. polygyrus bakeri 调节肠道 DC 功能，使其具有耐受性。这似乎是 H. polygyrus bakeri 抑制结肠炎的重要机制。IFN-γ 和 IL-17 是致结肠炎的。这些 DC 阻断肠道 Ag 特异性 IFN-γ/IL-17 T 细胞反应的能力也很重要。
