DEVELOPMENT AND FUNCTION OF INTESTINAL T-LYMPHOCYTES

胃肠道是许多病原体的入口， 毒素，并作为一个重要的感染部位，在健康和 免疫受损的宿主 一个精心设计的特异性免疫系统， 体液和细胞成分的结合维持了细胞的完整性。 小肠抵抗微生物入侵。 然而，大部分 特异性粘膜免疫细胞臂的功能潜力 是很难理解的。 该提案描述了一项研究计划， 小鼠呼肠孤病毒感染，以扩大我们对粘膜 细胞免疫 这项工作将侧重于分析 呼肠孤病毒感染对病毒特异性 上皮内淋巴细胞（IEL）。发展和功能 IEL和其他肠道淋巴细胞之间的关系也将被 通过比较病毒特异性细胞毒性IEL的特异性 和其他肠道T细胞出现在肠道呼肠孤病毒感染后 感染 此外，还比较了α/β家族 抗原的T细胞受体（TCR），其在病毒特异性 IEL和其他粘膜淋巴细胞将使用流式细胞仪进行检测。 分析。 胃粘膜淋巴细胞在体内的功能活性 还将检查对肠呼肠孤病毒感染的反应。 的 不同粘膜淋巴细胞群的增殖能力 在肠道攻击后的体内将通过测量 胸苷类似物5-溴-2 ′脱氧尿苷的体内掺入。 小鼠肠道淋巴细胞的细胞因子和细胞因子mRNA产生 肠道致敏的小鼠也将提供对效应子 病毒感染后粘膜T细胞的功能。 最后， 实验提出了检查肠道免疫的沼泽， 不产生CD 8 + α/β TCR+淋巴细胞。 这项工作将提供 更好地了解CD 8+肠道T细胞在免疫中的作用， 粘膜]免疫反应。 这项工作对于了解大肠癌的发病机制具有重要意义。 引起胃肠道疾病的微生物，如轮状病毒， 肠道致病菌以及引起全身性疾病的病原体 但通过粘膜表面进入 免疫缺陷病毒（HIV）。 除了重要的 传染病，这项工作具有广泛的影响， 治疗全身和局部自身免疫性疾病和癌症。 它 粘膜T细胞可能在控制和/或 加剧自身免疫性疾病和癌症;然而， 肠道T细胞在这些疾病中的作用。 拟议的研究 在这一良好的表征系统将提供新的，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.