CD8 in the Immunological Synapse and in Thymocyte Death
CD8 在免疫突触和胸腺细胞死亡中的作用
基本信息
- 批准号:6780797
- 负责人:
- 金额:$ 34.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-05-01 至 2005-04-30
- 项目状态:已结题
- 来源:
- 关键词:MHC class I antigenSDS polyacrylamide gel electrophoresisT cell receptorantigen presentationantigen presenting cellapoptosisbiological signal transductioncell cell interactioncrosslinkcytotoxic T lymphocytegenetically modified animalsglycosylationhelper T lymphocytelaboratory mouseligandsphosphorylationpolymerase chain reaction
项目摘要
DESCRIPTION (provided by applicant): During the interaction of T cells with antigen presenting cells (APCs), receptors and intracellular proteins translocate into the contact region known as the Immunological Synapse (IS). In CD4 T cells IS formation can readily be rendered independent of CD4 by increasing the amount of antigenic peptide whereas the same does not hold true for CD8 T cells. In addition, CD4 rapidly moves out of the center of the IS whereas we do not observe any such clearance of CD8. In this proposal we shall examine the IS of CD8 T cells interacting with APCs. In particular we shall focus on the requirement of the CD4/8 co-receptor and on the movement of both antigenic and non-antigenic MHC class I molecules. We shall also examine SMAC formation in immature thymocytes during a CD8 mediated, TCR independent interaction with APCs.
It has been demonstrated that MHC I tetramers can bind to CD8 on DP thymocytes in a TCR independent manner. This binding event has been attributed to a developmentally regulated difference in the glycosylation of CD8 on DP thymocytes compared to CD8 single positive thymocytes and peripheral T cells. In contrast there is no evidence for TCR independent binding of MHC class II tetramers to CD4 on DP thymocytes. The implications and/or biological relevance of this event have not been determined. Recently we have found that antibody mediated cross-linking of CDS, but not CD4, results in rapid apoptosis of CD4 CD8 (DP) thymocytes. Treatment with the phorbol ester, PMA, prevents the induction of apoptosis resulting from CD8 cross-linking. We hypothesize that the ligation of CD8 by physiological ligands in the absence of TCR engagement leads to the death of DP thymocytes during T cell development.
In this application we shall further characterize the induction of apoptosis in DP thymocytes by CD8 antibodies and also investigate whether classical or non-classical MHC class I molecules can induce apoptosis in DP thymocytes in a TCR independent manner. These studies will incorporate 4 specific aims: (1) To determine whether CD8 behaves as a co-receptor within the immunological synapse, for the activation of peripheral T cells (2) To determine the biochemical events leading to the CD8 mediated death of DP thymocytes; (3) To determine the mechanism by which treatment with PMA prevents CD8 mediated death in DP thymocytes; (4) To determine whether CD8 mediated death has a physiological function.
描述(由申请人提供):在T细胞与抗原呈递细胞(APC)相互作用期间,受体和细胞内蛋白质移位到称为免疫突触(IS)的接触区域。在CD 4 T细胞中,通过增加抗原肽的量,可以容易地使IS形成不依赖于CD 4,而对于CD 8 T细胞则不是如此。此外,CD 4迅速移出IS中心,而我们没有观察到任何这样的CD 8清除。在这个提议中,我们将研究与APC相互作用的CD 8 T细胞的IS。特别是,我们将重点关注CD 4/8辅助受体的需求以及抗原性和非抗原性MHC I类分子的运动。我们还将研究在CD 8介导的、TCR独立的与APC的相互作用过程中,未成熟胸腺细胞中SMAC的形成。
已经证明,MHC I四聚体可以以TCR非依赖性方式与DP胸腺细胞上的CD 8结合。该结合事件归因于与CD 8单阳性胸腺细胞和外周T细胞相比,DP胸腺细胞上CD 8糖基化的发育调节差异。相反,没有证据表明MHC II类四聚体与DP胸腺细胞上的CD 4的TCR独立结合。尚未确定该事件的影响和/或生物学相关性。最近,我们发现抗体介导的CDS交联,而不是CD 4,导致CD 4-CD 8(DP)胸腺细胞的快速凋亡。用佛波醇酯PMA处理可防止由CD 8交联引起的细胞凋亡的诱导。我们推测,在没有TCR参与的情况下,CD 8通过生理配体的连接导致T细胞发育期间DP胸腺细胞的死亡。
在本申请中,我们将进一步表征CD 8抗体诱导DP胸腺细胞凋亡,并研究经典或非经典MHC I类分子是否可以以TCR非依赖性方式诱导DP胸腺细胞凋亡。这些研究将包括4个具体目标:(1)确定CD 8是否作为免疫突触内的辅助受体,用于活化外周T细胞;(2)确定导致DP胸腺细胞中CD 8介导的死亡的生化事件;(3)确定PMA治疗预防DP胸腺细胞中CD 8介导的死亡的机制;(4)确定CD 8介导的死亡是否具有生理功能。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP.
- DOI:10.4049/jimmunol.1100088
- 发表时间:2011-09-01
- 期刊:
- 影响因子:0
- 作者:Jin L;Hill KK;Filak H;Mogan J;Knowles H;Zhang B;Perraud AL;Cambier JC;Lenz LL
- 通讯作者:Lenz LL
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{{ truncateString('TERRY A POTTER', 18)}}的其他基金
CD8 Mediated Apoptosis During T Cell Development
T 细胞发育过程中 CD8 介导的细胞凋亡
- 批准号:
7154097 - 财政年份:2004
- 资助金额:
$ 34.11万 - 项目类别:
CD8 Mediated Apoptosis During T Cell Development
T 细胞发育过程中 CD8 介导的细胞凋亡
- 批准号:
6986117 - 财政年份:2004
- 资助金额:
$ 34.11万 - 项目类别:
CD8 Mediated Apoptosis During T Cell Development
T 细胞发育过程中 CD8 介导的细胞凋亡
- 批准号:
7320666 - 财政年份:2004
- 资助金额:
$ 34.11万 - 项目类别:
CD8 Mediated Apoptosis During T Cell Development
T 细胞发育过程中 CD8 介导的细胞凋亡
- 批准号:
6869103 - 财政年份:2004
- 资助金额:
$ 34.11万 - 项目类别: