PROINFLAMMATORY CYTOKINES BLOCK T CELL DEATH IN VIVO

多年来，众所周知，将抗原注射到脑部 动物导致CD_4~+T细胞的活化和增殖 细胞。一旦激活的T细胞克隆扩增到最大 水平，他们中的大多数会通过细胞凋亡而死亡。本次活动 提出了一个问题，即抗原诱导的T细胞如何能够长期存活 足够发育成记忆细胞。因此，这些T细胞中的许多肯定是 能够抵抗死亡，否则记忆反应指向 抗原永远不会出现。最近，有研究表明，T细胞 面对炎症反应时的克隆性扩张可防止 活化的T细胞死亡。因此，对抗原有反应的T细胞 在发炎部位将免于激活诱导的死亡。它 已经提出激活的T细胞接收生存信号 这解除了对死亡计划的管制。例如，共同注入一个 抗原与致炎细菌的副产物， 脂多糖(LPS)，导致T细胞长期存活 抗原反应细胞。此外，注射脂多糖可使这些 抵抗基于Fas死亡的细胞。T细胞存活的本质 信号未知。该项目中的实验旨在 揭开这一信号的根基。然而，众所周知，内毒素 不会直接调节激活的T细胞，因此，必须 是与激活的T细胞相互作用的下游介质，并 解开他们的死亡之路。在这项研究中，我们将确定 内毒素诱导的因子是抢救必不可少的因素 抗原激活的T细胞免于死亡。无论是体内还是体外 将进行实验以确定哪些细胞因子是由 脂蛋白对于阻断死亡是必不可少的，哪些死亡途径是 在被拯救的T细胞中被解除了调控。健康免疫系统的标志 是区分自身抗原和外来抗原的能力。所有目标 通常会发生对自身抗原耐受性的崩溃，这可能会导致 自身免疫性疾病。在许多情况下，自身免疫与 炎症反应及其对适应性的影响 豁免权还没有得到很好的理解。这里描述的研究将导致 为了更好地理解炎症性疾病与 过程和T细胞存活。最终，这些研究可能会提供一种 更好地了解T细胞是如何被激活以保护宿主免受 一种侵袭性病原体和T细胞如何在 并成为自身反应。

For many years it has been well known that injection of antigen into animals leads to the activation and proliferation of CD4 bearing T cells. Once the activated T cells have clonally expanded to a maximal level, the majority of them go on to die via apoptosis. This event raises the problem of how antigen-primed T cells ever survive long enough to develop into memory cells. Thus many of these T cells must be able to resist death otherwise a memory response directed towards the antigen would never occur. Recently, it has been shown that T cell clonal expansion in the face of an inflammatory response prevents the death of activated T cells. Therefore, T cells that respond to antigen at an inflammatory site will be spared from activation-induced death. It has been proposed that the activated T cells receive a survival signal which deregulates the death program. For example, co-injection of an antigen with the pro-inflammatory bacterial byproduct, lipopolysaccharide (LPS), leads to long-term T cell survival of the antigen responsive cells. Furthermore, LPS injection conditions these cells to resist FAS-based death. The nature of the T cell survival signal is unknown. The experiments in this project are designed to uncover the underpinnings of this signal. It is known, however, that LPS does not directly condition the activated T cell, therefore, there must be downstream mediators that interact with the activated T cells and uncouple their death pathways. In this study we will determine which factors induced by lipopolysaccharide are essential for rescuing antigen-activated T cells from death. Both in vivo and in vitro experiments will be conducted to determine which cytokines induced by LPS are essential to block death and which death pathways are deregulated in the rescued T cells. A hallmark of a health immune system is the ability to discern self antigen from foreign antigen. All to often a breakdown in tolerance to self antigen occurs which can lead to autoimmune disease. In many cases autoimmunity is associated with inflammatory responses and the effects of inflammation on adaptive immunity are not well understood. The studies described here will lead to a better understanding of the relationship between inflammatory processes and T cell survival. Ultimately these studies may provide a better understanding on how T cells are activated to protect a host from an invading pathogen and how T cells fail self tolerance in the periphery and become autoreactive.