Oral Pathogens and Dendritic Cell Subsets

描述（由申请人提供）：作为复杂生物膜的一部分，牙龈卟卟菌具有独特的感染人口腔黏膜粘膜下区域的能力，因此它与CP中有效的抗原呈递细胞树突状细胞（dc）原位结合。这些dc与CD4+ T细胞形成有组织的免疫偶联物，称为口腔淋巴灶或OLF。因此，dc对牙龈卟啉菌感染的免疫调节功能是我们实验室非常感兴趣的。P. gingivalis表达一种不寻常的免疫调节LPS和两种纤维粘附素：67 kDa的mfa-1（次要）纤维和41 kDa的fimA（主要）纤维。我们发表的研究表明，牙龈假单胞菌的小菌毛靶向c型凝集素受体DC特异性ICAM-grabbing non-integrin （DC- sign）进入DC。牙龈假单胞菌被大量带入尚未确定的富含dc - sign的细胞内室，在那里牙龈假单胞菌看起来基本上是完整的和有活力的。此外，小毛在树突状细胞中诱导免疫抑制细胞因子和共刺激分子谱，树突状细胞诱导Th2效应反应。我们现在纯化了原生小菌毛，它似乎是糖基化的，并形成了200纳米的类似菌毛的链，通过电子显微镜显示。主要菌毛也促进牙龈假单胞菌进入dc，但DC-SIGN不参与其中。这些dc产生高水平的IL-12p70、IL-23和IL-6，并诱导强烈的CD4+幼稚T细胞增殖。T细胞响应主要的菌毛似乎是Th17细胞：分泌IL-17和IFN3。因此，这项更新应用的目的是确定牙龈假单胞菌的主要和次要菌毛在人类牙龈假单胞菌胞内命运中的作用（目的1），牙龈假单胞菌激活的dc中的信号通路（目的2）以及牙龈假单胞菌在dc中引发的T细胞效应反应（目的3）。这些持续研究的总体目标是确定这种口腔黏膜病原体如何能够在dc中持续存在并调节dc介导的免疫反应的机制。

DESCRIPTION (provided by applicant): While part of a complex biofilm, P. gingivalis is uniquely able to infect the submucosal regions of the human oral mucosa whereupon it associates in situ with the potent antigen presenting cells dendritic cells (DCs) in CP. These DCs form organized immune conjugates with CD4+ T cells, called oral lymphoid foci or OLF. The immunomodulatory functions of DCs in response to P. gingivalis infection is thus of intense interest in our laboratory. P. gingivalis expresses an unusual immunomodulatory LPS and two fimbrial adhesins: the 67 kDa mfa-1 (minor) fimbriae and the 41 kDa fimA (major) fimbriae. Our published studies indicate that the minor fimbriae of P. gingivalis targets the C-type lectin receptor DC- specific ICAM-grabbing non-integrin (DC-SIGN), for entry into DCs. P. gingivalis is taken into as yet unidentified DC-SIGN-rich intracellular compartments in large numbers, where P. gingivalis appear essentially intact and viable. Moreover, the minor fimbriae induce an immunosuppressive cytokine and costimulatory molecule profile in DCs and the DCs induce a Th2 effector response. We have now purified the native minor fimbriae and it appears to be glycosylated and forms fimbrial-like 200 nm strands, revealed by electron microscopy. The major fimbriae also enhance entry of P. gingivalis into DCs, but DC-SIGN is not involved. These DCs produce high levels of IL-12p70, IL-23 and IL-6 and induce strong CD4+ naive T cell proliferation. The T cells in response to major fimbriae appear to be Th17 cells: secreting IL-17 and IFN3. The objectives of this renewal application therefore are to determine the roles of minor and major fimbriae of P. gingivalis in the intracellular fate of P. gingivalis within human DCs (Aim 1), the signaling pathways in DCs activated by P. gingivalis (Aim 2) and the T cell effector responses elicited in DCs by P. gingivalis (Aim 3). The overall goal of these continuing studies is to identify the mechanisms for how this oral mucosal pathogen is able to persist in DCs and modulate DC-mediated immune responses.