Role of intraepithelial T cells in Toxoplasma gondii-induced inflammatory ileitis

描述（由申请人提供）：本申请的广泛、长期目标是了解机会性原生动物病原体刚地弓形虫感染期间引起肠道炎症病理的原因。最终，这将有助于开发合理的治疗策略，以治疗由人类黏膜免疫失调引起的炎症性肠病。C57BL/6系小鼠经口腔感染弓形虫后，迅速引发类似克罗恩病的病理反应，其特征是1型细胞因子过量产生，导致小肠上皮广泛坏死。CD4+ T细胞的致病群体被认为是疾病的介质。其他模型系统的研究也提示CD8+ T淋巴细胞的参与。上皮内淋巴细胞（IEL）是肠粘膜T细胞的一个主要亚群，其中大多数表达CD8分子。这一提议的假设是，失调的IEL反应在弓形虫引发的疾病发病机制和人类疾病中发挥重要作用。为了验证这一假设，具体的目的是从刚地弓形虫感染的小鼠中分离出IEL及其亚群，评估它们产生促炎性和抗炎性细胞因子的能力，并确定它们对感染和未感染靶细胞的细胞毒性活性。另一个目的是确定来自感染小鼠的IEL是否将病理转移到感染和未感染的受体，如果是这样，这是否依赖于IEL细胞因子的产生或细胞毒性活性。我们还将确定IEL本身是否足以引起病理，或者它们是否通过触发致病性固有层CD4+ T细胞起作用。实现这些目标有望有助于更深入地了解实验性感染以及临床疾病期间引发的IBD发病机制。

DESCRIPTION (provided by applicant): The broad, long-term objective of this application is to understand causes of intestinal inflammatory pathology induced during infection with the opportunistic protozoan pathogen Toxoplasma gondii. Ultimately, this will enable development of rational treatment strategies for inflammatory bowel diseases caused by dysregulated mucosal immunity in humans. Oral infection of C57BL/6 strain mice with Toxoplasma rapidly triggers a Crohn's disease-like pathology, characterized by overproduction of Type 1 cytokines leading to extensive necrosis in the small intestinal epithelium. Pathogenic populations of CD4+ T cells are believed to be mediators of disease. Studies in other model systems also suggest involvement of CD8+ T lymphocytes. Intraepithelial lymphocytes (IEL) are a major subset of T cells in the intestinal mucosa, the majority of which express the CD8 molecule. The hypothesis underlying this proposal is that dysregulated IEL responses play an important role in disease pathogenesis triggered by Toxoplasma and in human disease. To test this hypothesis, the specific aims are to isolate IEL and their subpopulations from T. gondii-infected mice and evaluate their ability to produce pro- and anti-inflammatory cytokines, as well as determining their cytotoxic activity on infected and noninfected target cells. Another aim is to determine if IEL from infected mice transfer pathology to infected and noninfected recipients, and if so whether this is dependent upon IEL cytokine production or cytotoxic activity. We will also determine if IEL are sufficient to cause pathology themselves, or if they act by triggering pathogenic lamina propria CD4+ T cells. Achieving these aims can be expected to contribute to a deeper understanding of IBD pathogenesis triggered by experimental infection, as well as during clinical disease. RELEVANCE: Chronic inflammatory bowel disease is a widespread and serious condition with increasing incidence in developed countries. Factors involved in disease pathogenesis are not well understood. We expect to gain insight into immunological causes of disease in humans by using Toxoplasma gondii infection as a trigger. The ultimate goal is to develop improved treatments for disease.