CONTROL OF NK & T CELLS BY TGF DURING VIRAL INFECTION

该项目的目标是表征“关闭”急性 体内自然杀伤（NK）细胞和T淋巴细胞应答。 NK细胞 T淋巴细胞在急性期被激活并进行增殖， 病毒感染 两种反应的动力学是不同的， 然而，NK细胞应答较早，而T细胞应答较晚。 紧张 这两种反应的调节表明，不仅重要的是 “关闭”，但也“关闭”NK细胞和T细胞增殖， 适当的时候。 申请中提出的研究基于 有趣的新数据表明，TGF-β在病毒感染过程中被诱导， 感染和NK细胞增殖是非常敏感的， 由这些因素介导的抑制。 在此提出的实验 本申请将使用小鼠的淋巴细胞实验感染， 脉络丛脑膜炎病毒（LCMV），以表征调节机制 急性淋巴细胞增殖在病毒感染，并评估 激活这些途径对随后的病毒抵抗的后果 感染 本文将对以下几个方面进行评价：（1）在 体内诱导NK细胞和T淋巴细胞增殖抑制介导 不同形式的TGF-β，（2）分化的机制， NK和T细胞亚群对TGF-β介导的抑制的敏感性， (3)在感染过程中产生各种形式的TGF-β，（4） 表型的细胞群体，使这些因素在体内，（5）的作用， 调节NK细胞和/或T淋巴细胞的内源性产生的TGF-β 体内增殖，和（6）诱导TGF-β的结果， 在LCMV感染期间，在随后的鼠感染中 巨细胞病毒（MCMV）。 将采取多方面的办法， 这个项目 生物化学研究将描述 对TGF-β的不同敏感性。 各种形式的表达 将通过分子研究来检查感染期间TGF-β的表达。 在 原位杂交和 将进行免疫组织化学研究， 检测不同脾白细胞内TGF-β的表达 感染后的亚群。 TGF-β在调节细胞凋亡中的生理作用 急性淋巴细胞增殖反应，并有助于增加 将在整个动物中评价对感染的易感性。 的 从这些研究中获得的信息将导致更好的 了解自然发生的调节过程， 体内急性淋巴细胞增殖。 此外，他们将提供 关于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点，以提高或 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.