Th17 cell regulation of intestinal IgA production

描述（由申请方提供）：免疫球蛋白A（伊加）已被证明在粘膜免疫防御中至关重要。肠道伊加可以通过T细胞依赖性和T细胞非依赖性途径产生，然而，每种途径的相对重要性以及它们如何调节仍然很大程度上不清楚。产生IL-17的CD 4 + T（Th 17）细胞最近被定义为一种独立的效应T细胞谱系，在宿主防御某些感染因子以及在一些自身免疫性疾病的发病机制中是重要的。虽然大量的伊加和Th 17细胞都组成性地存在于肠道中，但很少有数据说明这些系统中的每一个如何响应微生物群的抗原，或者这两个系统是否在这种努力中相互作用。我们的初步数据发现IL-17 R缺陷小鼠肠道伊加产生受损。相反，Th 17细胞的过继转移诱导TCR <$xd-/-小鼠的肠道伊加产生，表明Th 17细胞在肠道伊加产生中起重要作用。Th 17细胞调节肠伊加应答的机制是未知的，并且是本申请的主题。最近，我们确定了肠道细菌鞭毛蛋白，这存在于肠腔，作为免疫显性抗原在实验性结肠炎和克罗恩病患者。我们已经产生了一个TCR转基因小鼠系，是特定的CBir 1鞭毛蛋白，这些细菌鞭毛蛋白之一。我们将CBir 1 Tg小鼠与IL-17 F-Thy 1.1报告小鼠和IFN？Thy1.1报告基因小鼠。有了这些新的小鼠和试剂，我们将研究Th 17细胞如何调节肠道伊加反应，以及假定的Th 17-伊加途径是否针对使用霍乱毒素（CT）作为替代病原体的病原体和毒素。我们推测1）Th 17细胞通过IL-17、IL-21以及CD 40 L-CD 40相互作用的机制促进肠道伊加的产生; 2）Th 17-伊加途径介导粘膜对霍乱毒素的伊加应答，这依赖于霍乱毒素诱导IL-6的产生。

DESCRIPTION (provided by applicant): Immunoglobulin A (IgA) has been shown to be critical in mucosal immune defense. Intestinal IgA can be produced by both T cell-dependent and T cell-independent pathways, however, the relative importance of each and how they are regulated are still largely unclear. IL-17-producing CD4+ T (Th17) cells have recently been defined as a separate effector T cell lineage, important in host defense against certain infectious agents, as well as in the pathogenesis of some autoimmune diseases. Although high amounts of IgA and Th17 cells are both present constitutively in intestine, there is sparse data that addresses how each of these systems respond to antigens of the microbiota, or whether these two systems interact in that effort. Our preliminary data found impaired intestinal IgA production in IL-17R deficient mice. Conversely, adoptive transfer of Th17 cells induced intestinal IgA production in TCR¿xd-/- mice, indicating that Th17 cells play an important role in intestinal IgA production. The mechanism(s) of Th17 cell regulation of intestinal IgA responses is unknown, and the subject of this application. We recently identified enteric bacterial flagellins, which present in intestinal lumen, as immunodominant antigens in experimental colitis and in patients with Crohn's disease. We have generated a TCR transgenic mouse line that is specific for CBir1 flagellin, one of these commensal bacterial flagellins. We have crossed CBir1 Tg mice with IL-17F-Thy1.1 reporter mice and IFN?- Thy1.1 reporter mice. With these novel mice and reagents in hand, we will investigate how Th17 cells regulate intestinal IgA responses, and whether the putative Th17-IgA pathway is directed toward pathogens and toxins using cholera toxin (CT) as a surrogate pathogen. We hypothesize that 1) Th17 cells promote intestinal IgA production via mechanisms involving IL-17, IL-21, as well as CD40L-CD40 interactions; 2) Th17-IgA pathway mediates mucosal IgA response to cholera toxin, which depends on cholera toxin induction of IL-6 production.