CONTROL OF NK & T CELLS BY TGF DURING VIRAL INFECTION

这个项目的目标是描述“关闭”急性的通路。 体内自然杀伤(NK)细胞和T淋巴细胞反应。两种NK细胞 急性加重期T淋巴细胞被激活并发生增殖 病毒感染。这两种反应的动力学是不同的， 然而，NK细胞反应较早，而T细胞反应较晚。紧绷的 对这两种反应的监管表明，不仅重要的是 “关闭”也是为了“关闭”NK细胞和T细胞的增殖 合适的时机。申请书中建议的研究是基于 有趣的新数据表明，转化生长因子-β是在病毒感染过程中诱导的 感染和NK细胞增殖对 由这些因素介导的抑制作用。这项研究中提出的实验 应用将用实验性感染的小鼠的淋巴细胞 脉络膜脑膜炎病毒(LCMV)调控机制的研究 病毒感染时的急性淋巴细胞增殖和评估 激活这些通路对后续病毒的抵抗力的后果 感染。将评估以下内容：(1)In的灵敏度 体内诱导NK细胞和T淋巴细胞增殖抑制介导的研究 通过不同形式的转化生长因子-β，(2)分化的机制 NK和T细胞亚群对转化生长因子-β介导的抑制的敏感性 (3)在感染期间产生各种形式的转化生长因子-β；(4) 细胞群体的表型使这些因子在体内，(5)作用 内源性转化生长因子-β对NK细胞和/或T淋巴细胞的调节作用 体内增殖，以及(6)诱导转化生长因子-β的后果， 在LCMV感染期间，关于随后与小鼠的感染 巨细胞病毒(MCMV)将使用多方面的方法来进行 这个项目。生物化学研究将确定 对转化生长因子-β的鉴别敏感性。各种形式的表达 将通过分子研究来检测感染过程中转化生长因子-β的变化。在……里面 将进行原位杂交和免疫组织化学研究 检测转化生长因子-β在不同脾白细胞中的表达 感染后的亚群。转化生长因子-β的生理调节作用 急性淋巴细胞增殖反应和在促进增加 对感染的敏感性将在整个动物中进行评估。这个 从这些研究中获得的信息将产生更好的 对自然发生的调控过程的理解 体内急性淋巴细胞增殖。此外，他们还将提供 对急性反应可能产生的免疫抑制后果的见解 病毒感染和可能的干预要点，以增强或 抑制免疫反应。

The goal of this project is to characterize pathways that "turn off" acute natural killer (NK) cell and T lymphocyte responses in vivo. Both NK cells and T lymphocytes are activated and undergo proliferation during acute viral infections. The kinetics of the two responses are different, however, NK cells respond early whereas T cells respond late. The tight regulation of these two responses suggest that it is not only important to "turn off" but also to "turn off" NK cell and T cell proliferation at appropriate times. The studies proposed in the application are based on interesting new data suggesting that TGF-betas are induced during viral infections and that NK cell proliferation is extremely sensitive to inhibition mediated by these factors. The experiments proposed in this application will use experimental infections of mice with lymphocytic choriomeningitis virus (LCMV) to characterize the mechanisms regulating acute lymphocyte proliferation during viral infections and to evaluate the consequences of activating such pathways on resistance to subsequent viral infection. The following will be evaluated: (1) the sensitivity of in vivo elicited NK cell and T lymphocyte proliferation to inhibition mediated by different forms of TGF-beta, (2) the mechanism for differential sensitivities of the NK and T cell subsets to TGF-beta-mediated inhibition, (3) the production of various forms of TGF-beta during infection, (4) the phenotype of cell populations make these factors in vivo, (5) the role of endogenously produced TGF-betas in regulating NK cell and/or T lymphocyte proliferation in vivo, and (6) the consequences of inducing TGF-betas, during LCMV infections, on subsequent infections with murine cytomegalovirus (MCMV). A multi-faceted approach will be used to carry out this project. Biochemical studies will characterize the mechanisms for differential sensitivities to TGF-betas. The expression of various forms of TGF-betas during infection will be examined by molecular studies. In situ hybridizations and immunohistochemical studies will be performed to examine the expression of the TGF-betas within different splenic leukocyte subsets post-infection. The physiological role of TGF-betas in regulating acute lymphocyte proliferative responses and in contributing to increased susceptibility to infections will be evaluated in whole animals. The information obtained from these studies will result in a better understanding of the naturally occurring regulatory processes controlling acute lymphocyte proliferation in vivo. Furthermore, they will provide insights as to possible immunosuppressive consequences of an acute response to viral infection and possible points of intervention to either enhance or inhibit the immune response.