CD4 T CELL ANERGY IN MURINE AIDS
小鼠艾滋病中的 CD4 T 细胞无能
基本信息
- 批准号:2109901
- 负责人:
- 金额:$ 9.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-07-01 至 2000-02-29
- 项目状态:已结题
- 来源:
- 关键词:AIDS Retroviridae T cell receptor anergy apoptosis biological signal transduction disease /disorder model flow cytometry genetic transcription helper T lymphocyte interleukin 2 interleukin 4 laboratory mouse leukocyte activation /transformation phosphatidylinositols phosphorylation polymerase chain reaction protein tyrosine kinase protooncogene tissue /cell culture tyrosine western blottings
项目摘要
BM5, a mixture of retroviruses induces a fatal immunodeficiency syndrome
when injected into C57BL/6 mice. The most interesting feature of this
disease is an absolute requirement for CD4 T cells for disease induction
and progression. Interestingly, as the disease sets in, CD4 T cells become
completely unresponsive to polyclonal and antigen-specific stimulations.
Moreover, BM5 retroviral mixture appears to either encode or stimulate an
endogenous superantigen which deletes Vbeta5.2 positive CD4 T cells in the
spleen and lymph nodes of infected animals. This model presents an ideal in
vivo system to study CD4 T cells that are rendered anergic by retroviral
infection because entire CD4 T cell population representing various Vbeta
TCRs is anergic and is not restricted to a few subsets of CD4 T cells.
We will take advantage of such a system to.study the process of anergy as
CD4 T cells steadily lose their capacity to proliferate or synthesize
cytokines in response to various stimuli. The initial approach is to
pinpoint the defective steps in the cascade of reactions that follow TCR
stimulation. We will test the possibility that there is an altered tyrosine
phosphorylation of substrates since it is the first step in signal
transduction and the involvement of tyrosine kinases such as p56 1ck, p59
fyn and phosphatases like CD45 in anergy. Other steps in signal
transduction namely, phosphoinositide hydrolysis and subsequent CA++
release and activation of PKC will be evaluated. Next, we will monitor the
expression of various costimulatory molecules on anergic and normal CD4 T
cells. In order to assess the role of costimulatory molecules in inducing
lymphokine gene expression, we will coculture anergic CD4 T cells with
anti-CD28 or provide APCs that have high expression of B7 and study the
effects on IL-2 and IL-4 gene transcription. In most superantigen induced
anergy systems, anergic cells undergo apoptosis when they are stimulated
via the TCR. Apoptosis is blocked in cells with elevated expression of bcl-
2 and is induced in cells with high c-myc expression. These observations
suggest that protooncogenes such as bcl-2 and c-myc have a major role in
maintaining anergic cells in vivo. We plan to study the expression of bcl-2
and c-myc in anergic CD4 T cells and their role in maintaining anergic CD4
T cells in vivo.
We believe a model system like BM5 retrovirus induced CD4 anergy will
enable us to design experiments to follow the course of CD4 T cells as they
progressively expand in vivo, yet fail to function and become anergic. This
system is well suited to study the biochemical events involved in signal
transduction, costimulation and finally apoptosis of anergic CD4 T cells.
逆转录病毒混合物BM 5引起致命性免疫缺陷综合征
当注射到C57 BL/6小鼠中时。最有趣的是
疾病是疾病诱导对CD 4 T细胞的绝对要求
和进步。有趣的是,随着疾病的发生,CD 4 T细胞
对多克隆和抗原特异性刺激完全无反应。
此外,BM 5逆转录病毒混合物似乎编码或刺激了一种新的逆转录病毒。
内源性超抗原,其删除了V5.2阳性CD 4 T细胞,
脾脏和淋巴结。该模型提出了一种理想的,
研究逆转录病毒致无能的CD 4 T细胞的体内系统
感染,因为整个CD 4 T细胞群代表各种V β
TCR是无反应性的,并且不限于CD 4 T细胞的少数亚群。
我们将利用这样一个系统to.study的无功过程,
CD 4 T细胞逐渐失去增殖或合成的能力
细胞因子对各种刺激的反应。最初的做法是
在TCR之后的级联反应中,
刺激.我们将测试是否有一个改变的酪氨酸
底物的磷酸化,因为它是信号转导的第一步。
转导和酪氨酸激酶如p56 1ck、p59
fyn和磷酸酶如CD 45在无能中的作用。信号中的其他步骤
转导,即磷酸肌醇水解和随后的CA++
将评价PKC的释放和活化。接下来,我们将监测
各种共刺激分子在无能和正常CD 4 T细胞上的表达
细胞为了评估共刺激分子在诱导细胞凋亡中的作用,
淋巴因子基因表达,我们将无反应性CD 4 T细胞与
抗CD 28或提供具有B7高表达的APC,并研究B7的表达。
对IL-2和IL-4基因转录的影响。在大多数超抗原诱导的
无反应性系统,无反应性细胞在受到刺激时发生凋亡
通过TCR。凋亡在bcl-2表达升高的细胞中被阻断,
2,并在具有高c-myc表达的细胞中诱导。这些观察结果
提示原癌基因如bcl-2和c-myc在
维持体内无反应性细胞。我们计划研究bcl-2的表达
和c-myc在无能性CD 4 T细胞中的表达及其在维持无能性CD 4 T细胞中的作用
体内T细胞。
我们相信,一个模型系统,如BM 5逆转录病毒诱导的CD 4无反应性,
使我们能够设计实验来跟踪CD 4 T细胞的过程,因为它们
在体内逐渐扩增,但不能发挥功能并变得无反应性。这
系统非常适合于研究信号中涉及的生化事件
转导、共刺激和最后的无反应性CD 4 T细胞凋亡。
项目成果
期刊论文数量(0)
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GIRIJA MURALIDHAR其他文献
GIRIJA MURALIDHAR的其他文献
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{{ truncateString('GIRIJA MURALIDHAR', 18)}}的其他基金
BD FACSCANTO FLOW CYTOMETER: BIOCHEMISTRY
BD FACSCANTO 流式细胞仪:生物化学
- 批准号:
7335097 - 财政年份:2006
- 资助金额:
$ 9.69万 - 项目类别:
BD FACSCANTO FLOW CYTOMETER: IMMUNOLOGY
BD FACSCANTO 流式细胞仪:免疫学
- 批准号:
7335096 - 财政年份:2006
- 资助金额:
$ 9.69万 - 项目类别: