Th17 cell regulation of intestinal IgA production

描述(由申请人提供)：免疫球蛋白A(IgA)已被证明在粘膜免疫防御中起关键作用。肠道免疫球蛋白A可通过T细胞依赖途径和T细胞非依赖途径产生，然而，每种途径的相对重要性以及它们是如何调控的在很大程度上仍不清楚。产生IL-17的CD4+T细胞(Th17)最近被定义为一种独立的效应性T细胞谱系，在宿主防御某些感染性物质以及一些自身免疫性疾病的发病机制中发挥重要作用。虽然肠道中都存在大量的IgA和Th17细胞，但很少有数据说明这两个系统如何对微生物区系的抗原做出反应，或者这两个系统是否在这一努力中相互作用。我们的初步数据发现，IL-17R缺陷小鼠的肠道免疫球蛋白A产生受损。相反，过继转移Th17细胞可诱导TCR？XD-/-小鼠肠道IgA的产生，表明Th17细胞在肠道IgA的产生中起重要作用。Th17细胞调节肠道免疫球蛋白A应答的机制(S)尚不清楚，本应用的主题是。我们最近发现肠道细菌鞭毛蛋白存在于肠腔中，是实验性结肠炎和克罗恩病患者的免疫优势抗原。我们已经建立了一个针对CBir1鞭毛蛋白的TCR转基因小鼠系，CBir1鞭毛蛋白是这些共生细菌鞭毛蛋白之一。我们已经将CBir1Tg小鼠与IL-17F-Thy1.1报告鼠和干扰素？-Thy1.1报告鼠杂交。有了这些新的小鼠和试剂，我们将研究Th17细胞如何调节肠道IgA反应，以及假定的Th17-IgA途径是否以霍乱毒素(CT)作为替代病原体指向病原体和毒素。我们假设1)Th17细胞通过IL-17、IL-21以及CD40L-CD40相互作用促进肠道IgA的产生；2)Th17-IgA途径介导黏膜对霍乱毒素的IgA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.