T cell responses to chronic bacterial infection

描述（由申请人提供）：许多病原体，如人类免疫缺陷病毒（HIV）和结核分枝杆菌（Mtb），能够在面对持续的免疫反应时建立持续的慢性感染。然而，我们对免疫反应如何长期维持慢性感染或免疫反应强度与病原体负荷之间的关系知之甚少。在这里，我们建议使用结核分枝杆菌感染的小鼠模型来解决持久性T细胞反应的基本机制。已经确定，尽管CD4+ T细胞在控制人类和小鼠的结核分枝杆菌感染中发挥了重要作用，但这些细胞不能完全清除感染，从而使细菌在肺部持续存在（细菌的“设定值”）。我们的初步数据表明，T细胞对慢性结核杆菌感染的反应是动态的，其特征是快速和持续的CD4+ T细胞增殖和细胞因子的产生。然而，我们不知道这种强大的T细胞反应是如何长期维持的。特别是，关于效应T细胞是否持续增殖或耗尽，静止记忆T细胞池是否在感染远端建立，或CD8+ T细胞的相对贡献，我们知之甚少。为了解决这些问题，我们开发了一种T细胞受体（TCR）转基因小鼠特异性的Mtb分泌抗原。我们将利用这些小鼠来确定持续T细胞反应的机制，并确定如何维持T细胞反应和细菌设定值之间的平衡。在目的1中，我们将确定在慢性抗原暴露为特征的持续性结核分枝杆菌感染期间，抗原特异性T细胞反应是如何维持的。基本的方法是将未成熟的转基因T细胞转移到被结核分枝杆菌气溶胶感染的小鼠体内，然后用流式细胞术追踪供体细胞。这将使我们能够在感染过程中详细确定抗原特异性CD4+ T细胞的分布、寿命、表型和功能。在目标2中，我们将确定抗原特异性T细胞调节细菌设定值的程度。这将通过确定我们可以通过改变抗原特异性CD4+ T细胞的数量和/或功能来调节细菌负荷设定值的程度来实现。此外，我们将确定CD4+ T细胞是否是IFN的来源？在调节细菌负荷设定值。同时，我们还将确定抗原特异性CD8+ T细胞对保护性免疫的贡献程度。通过精确定义CD4+和CD8+ T细胞的作用，这些研究将对开发促进加强结核分枝杆菌感染控制的疫苗具有重要意义。

DESCRIPTION (provided by applicant): Many pathogens, such as the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (Mtb) are able to establish chronic infections that persist in the face of a persistent immune response. Yet we have little understanding of how immune responses can be maintained to chronic infections over the long-term or the relationship between the magnitude of the immune response and pathogen load. Here we propose to address the basic mechanisms underlying persistent T cell responses using a mouse model of Mtb infection. It has been established that although CD4+ T cells play an instrumental role in the control of Mtb infection in humans and mice, these cells are not able to completely clear the infection, thereby allowing the bacteria to persist in the lung (the bacterial "setpoint"). Our preliminary data show that the T cell response to chronic Mtb infection is dynamic and characterized by rapid and continual CD4+ T cell proliferation and cytokine production. However, we don't know how this robust T cell response is maintained over the long term. In particular, we have very little information on whether the effector T cells continually proliferate or become exhausted, whether resting memory T cell pools are established at sites distal to the infection, or the relative contribution of CD8+ T cells. To address these issues we have developed a T cell receptor (TCR) transgenic mouse specific for an Mtb secreted antigen. We will take advantage of these mice to identify the mechanisms underlying persistent T cell responses and determine how the balance between the T cell response and bacterial setpoint is maintained. In Aim 1, we will determine how antigen-specific T cell responses are maintained during a persistent Mtb infection characterized by chronic antigen exposure. The basic approach will be to transfer naive transgenic T cells into mice that have been aerosol-infected with Mtb and then track the donor cells by flow cytometry. This will allow us to determine the distribution, longevity, phenotype and function of antigen-specific CD4+ T cells in detail during the course of infection. In Aim 2, we will determine the extent to which antigen-specific T cells regulate the bacterial setpoint. This will be accomplished by determining the extent to which we can modulate the bacterial load setpoint by altering the number and/or function of antigen-specific CD4+ T cells. In addition, we will determine whether CD4+ T cells are the source of IFN? in regulating the bacterial load setpoint. In parallel, we will also determine the extent to which antigen-specific CD8+ T cells contribute to protective immunity. By precisely defining the contribution of both CD4+ and CD8+ T cells, these studies will have important implications for the development of vaccines that promote enhanced control of Mtb infection. Relevance: Pathogens that mediate chronic infections, such as Mtb, are a major public heath threat. The proposed studies will generate information on the maintenance of protective T cell responses and will facilitate the development of new vaccines and therapies against this class of pathogens.