How CD2 and CD28 Determine Susceptibility to P. Carinii

CD2 和 CD28 如何确定对卡氏疟原虫的易感性

基本信息

批准号：
6627834
负责人：
Jonathan M. Green
金额：
$ 22.95万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-15 至 2005-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (Provided by the applicant): Loss of CD4+ T cell number or function may render individuals susceptible to opportunistic infection such as P. carinii pneumonia (PCP). This is exemplified by Human Immunodeficiency Virus infection, but also complicates other diseases in which normal immune cell function is perturbed. Although both observational and experimental data indicate that the CD4+ T cell is a critical determinant of the outcome of infection with Pneumocystis, the precise manner in which this effect is exerted is less clear. In addition to direct effector function, CD4+ T cells influence the function of other cells such as B cells, macrophages and cytolytic T cells through both soluble mediators as well as via direct intercellular interactions. Derangement in any of these elements of the immune response may lead to increased susceptibility to opportunistic infection. T cell activation is determined not only by engagement of the T cell antigen receptor, but also by theengagement of other receptors, termed costimulatory receptors. CD2 and CD28 are two well-described costimulatory molecules. Mice deficient in CD2 have little discernible phenotype on examination of T cell function. T cells from CD28-deficient mice have reduced proliferative responses and cytokine secretion. as well as impaired survival, but previously have not been noted to be susceptible to opportunistic infection. We have generated mice deficient in both CD2 and CD28. These mice have a profound defect in T cell activation despite normal lymphocyte numbers and distribution. Furthermore, the CD2/CD28 double deficient mice spontaneously develop and succumb to infection with P. carinii. Mice deficient only in CD28 do not develop P. carinii following co-housing with infected animals, yet are susceptible if inoculated intratracheally. The defined genetic defect that results in defective T cell function despite normal T cell number provides us with a novel opportunity to examine the role of T cells response to P. carinii. Furthermore, the differential susceptibility of CD28-deficient mice to naturally acquired infection vs direct inoculation allows us to examine how route of infection influences the host response. To address this, we propose the following two specific aims: 1 ) Characterize the response of costimulation deficient mice to infection with Pneumocystis carinii. The experiments proposed in this aim will provide quantitative data defining the susceptibility of the costimulation deficient mice and the characteristics of the immune response mounted against them. 2) Determine if reconstitution of specific cellular elements enable clearance of P. carinii infection in costimulation deficient mice. In this aim we will restore specific aspects of the host response by adoptive transfer into the costimulation deficient mice to dissect what required elements of the host response are lacking in the costimulation deficient mice. Although the observation of severe P. carirzii pneumonia in the double knockout mice was unexpected, these mice provide us with a powerful tool to examine the role of costimulatory molecules in defense against this important opportunistic pathogen.

描述（申请人提供）：CD4+ T单元号或功能的丢失可能会使个人容易受到机会感染，例如P。 Carinii肺炎（PCP）。这是人类免疫缺陷病毒的例证感染，但也使其他疾病复杂化，其中正常免疫细胞功能受到干扰。虽然观察和实验数据表明CD4+ T细胞是结果的关键决定因素感染肺炎囊肿，这种效果的精确方式不太清楚。除了直接效应子功能，CD4+ T细胞还会影响其他细胞（例如B细胞，巨噬细胞和细胞溶解T细胞）的功能通过两个可溶性介体以及通过直接细胞间的互动。免疫反应的任何这些元素中的任何一个都可能导致对机会性感染的敏感性增加。 T细胞激活不仅是通过T细胞抗原的参与来确定的受体，也是通过其他受体的参与，称为cotumulation 受体。 CD2和CD28是两个描述良好的共刺激分子。老鼠 CD2缺乏在检查T细胞时几乎没有明显的表型功能。来自CD28缺陷小鼠的T细胞降低了增生反应和细胞因子分泌。以及生存受损，但以前没有被指出容易受到机会性感染的影响。我们已经产生了小鼠 CD2和CD28缺乏。这些小鼠在T细胞中有深刻的缺陷尽管淋巴细胞数和分布正常，但激活。此外， CD2/CD28双重缺陷小鼠自发发展并屈服于感染与P. carinii。仅在CD28中缺乏的小鼠不形成carinii 与受感染的动物共住房后，如果接种了节气内。定义的遗传缺陷，导致T细胞缺陷功能尽管正常T细胞号为我们为我们提供了新的机会检查T细胞对Carinii的反应的作用。此外， CD28缺陷小鼠自然获得的差异敏感性感染与直接接种，使我们能够检查感染路线影响宿主反应。为了解决这个问题，我们提出以下两个具体目的：1）表征共刺激不足小鼠对肺炎藻菌感染。此目标中提出的实验提供定量定义共刺激敏感性的定量数据不足的小鼠和免疫反应的特征他们。 2）确定重构特定的细胞元件是否可以启用 carinii感染的清除不足小鼠。在这个目标中我们将通过收养转移到不足的小鼠剖析宿主的必需要素无反应缺乏小鼠。虽然在双敲除小鼠中观察严重的Carirzii肺炎是出乎意料的是，这些小鼠为我们提供了一个强大的工具来检查防御这种重要的机会主义的共同刺激分子病原。