DEVELOPMENT AND FUNCTION OF INTESTINAL T-LYMPHOCYTES

胃肠道是许多病原体进入的门户， 毒素，并且是健康和健康的 免疫功能受损的宿主。一种精心设计的特定免疫系统，包括 体液成分和细胞成分的结合，保持了 小肠抗微生物入侵。然而，大部分 特异性粘膜免疫细胞臂的功能潜能 人们对此知之甚少。 这项建议描述了一项使用实验性肠道的研究计划 在小鼠体内感染呼肠孤病毒扩大了我们对粘膜的了解 细胞免疫。这项工作将集中于对影响的分析 呼肠孤病毒感染对病毒特异性发展的影响 上皮内淋巴细胞(IEL)。发展性和功能性 IEL与其他肠道淋巴细胞的关系也将是 比较病毒特异性细胞毒IEL的特异性 和肠道呼肠孤病毒后出现的其他肠道T细胞 感染。此外，α/β家族的比较 病毒特异性表达的T细胞抗原受体(TCR) IEL和其他粘膜淋巴细胞将使用流式细胞仪 分析。小鼠胃粘膜淋巴细胞的体内功能活性 还将检查对肠道呼肠孤病毒感染的反应。这个 不同群体粘膜淋巴细胞的增殖能力 肠道挑战后的活体内评估将通过测量 胸苷类似物5-溴-2‘-脱氧尿苷的体内掺入。 猪肠道淋巴细胞产生细胞因子及细胞因子mRNA的研究 肠道准备的小鼠也将提供对效应器的洞察。 病毒感染后粘膜T细胞的功能。最后， 建议进行实验以检验沼泽动物的肠道免疫功能。 不产生CD8+α/βTCR+淋巴细胞。这项工作将提供 更好地了解CD8+T细胞在肠道疾病中的作用 粘膜]免疫反应。 这项拟议的工作对于理解红斑狼疮的发病机制很重要。 引起胃肠道疾病的微生物，如轮状病毒和 肠道致病菌，以及引起系统性疾病的病原体 疾病，但通过粘膜表面进入，如人类 免疫缺陷病毒(HIV)。除了对 传染病，这项工作对开发具有广泛意义的 治疗全身和局部自身免疫性疾病和癌症。它 可能是粘膜T细胞在控制和/或 加剧自身免疫性疾病和癌症；但人们对此知之甚少 肠道T细胞在这些疾病中的作用。建议进行的研究 在这个特性良好的系统中将提供新的、关键的信息 T细胞在肠道免疫中的作用。

The gastrointestinal tract is the portal of entry for many pathogens and toxins and serves as a significant site of infection in both healthy and immunocompromised hosts. An elaborate specific immune system consisting of both humoral and cellular components maintains the integrity of the small intestine against microbial invasion. However, much of the functional potential of the cellular arm of specific mucosal immunity is poorly understood. This proposal describes a research plan that uses experimental enteric reovirus infection in mice to expand our understanding of mucosal cellular immunity. The work will focus on an analysis of the effects of reovirus infection on the development of virus-specific intraepithelial lymphocytes (IEL). The developmental and functional relationship between IEL and other intestinal lymphocytes will also be explored by comparing the specificity of virus-specific cytotoxic IEL and other intestinal T-cells that appear following enteric reovirus infection. In addition, a comparison of the families of alpha/beta T-cell receptors for antigen (TCR) that are expressed on virus-specific IEL and other mucosal lymphocytes will be made using flow cytometric analyses. The in vivo functional activity of mucosal lymphocytes in the response to enteric reovirus infection will also be examined. The capacity of distinct populations of mucosal lymphocytes to proliferate in vivo following enteric challenge will be assessed by measuring in vivo incorporation of the thymidine analog 5-bromo-2'deoxyuridine. Cytokine and cytokine mRNA production by gut lymphocytes from enterically primed mice will also provide insight into the effector function of mucosal T-cells following virus infection. Finally, experiments are proposed to examine enteric immunity in mire which do not produce CD8+ alpha/beta TCR+ lymphocytes. This work will provide a better understanding of the role of CD8+ intestinal T-cells in the mucosa] immune response. The proposed work is important for understanding the pathogenesis of microbes that cause gastrointestinal disease such as rotavirus and enteropathogenic bacteria, as well as pathogens that cause systemic disease but gain entry through mucosal surfaces such as human immunodeficiency virus (HIV). In addition to being important for infectious diseases, this work has broad implications for developing treatments for systemic and local autoimmune diseases and cancer. It is likely that mucosal T-cells play a major role in controliing and/or exacerbating autoimmune diseases and cancer; yet little is known about the role of intestinal T-cells in these diseases. The proposed studies in this well characterized system will provide new, critical information about the role of T-cells in intestinal immunity.