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Molecular Identification and Immunological Significance of I-J Molecule.

I-J 分子的分子鉴定和免疫学意义。

基本信息

批准号：
01440033
负责人：
TADA Tomio
金额：
$ 12.48万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

项目摘要

I-J has been an enigmatic molecule on T cells which undergoes a systematic somatic alteration according to the environmental major histocompatibility complex (MHC) during their ontogeny of T cells as demonstrated in radiation bone marrow chimeras and class II gene transgenic mice. Thus, I-J is not a direct product of an MHC gene as originally thought, but is an adaptive molecule to a self MHC polymorphism most likely to be a receptor-like molecule for self. In order to study the molecular nature of I-J, we have established a series of IL-2 dependent T cell clones from different haplotype origins including radiation bone marrow chimeras. They are either helper (Th) or suppressor (Ts) clones with different MHC restriction specificities. They are mostly CD4^+ Th and Ts clones except for a few CD8^+ Ts clones. Ts subtype was defined by its inability to produce both IL-2 and IL-4, lack of helper activity for B cells, and by its strong inhibitory activity for the antibody response of MHC-mat … More ched T and B cells.Many of the H-2^k-restricted clones were found to be positive for the staining with a monoclonal anti-I-J^K. Both I-A^k- and I-E^k- restricted clones derived from different origins including H-2^b- > H-2^k chimeras expressed the same I-J^k epitope. The I-J molecule was not co-modulated with TcR/CD3 complex.By immunoprecipitation and subsequent one- or two-dimensional gel analyses of the lysate of these T cell clones, I-J molecule was found to be a novel dimeric surface molecule of MW 86,000 composed of 43,000 glycopeptide subunits differing from TcR heterodimer, MHC class II antigen, and previously known dimeric proteins of T cells. A monomeric form also existed on some T cell clones. Protein sequencing and gene cloning approaches are now under way.The I-J polypeptide seems to play an important role in the regulation of early signal transduction in T cells after antigen-recognition. When T cell clones with the I-J^k epitope was pretreated with the monoclonal anti-I-J^k, the Ca^<++> influx induced by a subsequent stimulation with antigen-pulsed antigen-presenting cell was greatly inhibited. The Ca^<++> response induced by anti-TcR heterodimer but not by anti-CD3 or Con A was similarly inhibited by the anti-IーJ. The ligation of I-J molecules by intact antibody but not by Fab was required for the initiation of suppression. The pattern of inhibition of Ca^<++> influx was very similar to that observed in Th clones preincubated with Ts clones. These results indicate that the negative signal from I-J receptor may inhibit the expansion of self MHC-reactive T cells both in ontogeny and in periphery. Less

I-J是T细胞上的一种神秘分子，其在T细胞的个体发育期间根据环境主要组织相容性复合体（MHC）经历系统的体细胞改变，如在辐射骨髓嵌合体和II类基因转基因小鼠中所证明的。因此，I-J不是最初认为的MHC基因的直接产物，而是对自身MHC多态性的适应性分子，最有可能是自身的受体样分子。为了研究I-J的分子本质，我们建立了一系列来自不同单倍型来源的IL-2依赖性T细胞克隆，包括辐射骨髓嵌合体。它们是具有不同MHC限制性特异性的辅助（Th）或抑制（Ts）克隆。除少数CD 8 ^+ Ts克隆外，大部分为CD 4 ^+ Th和Ts克隆。Ts亚型的定义是它不能产生IL-2和IL-4，缺乏对B细胞的辅助活性，并通过其对MHC-mat抗体应答的强抑制活性来确定。 ...更多信息发现许多H-2 κ限制性克隆对单克隆抗I-J κ染色呈阳性。来自不同来源的I-A^k-和I-E^k-限制性克隆，包括H-2 ^b- > H-2 ^k嵌合体，表达相同的I-J^k表位。I-J分子不与TcR/CD_3复合物共调节，通过免疫沉淀和随后的一维或二维凝胶分析，这些T细胞克隆的裂解物被发现是一种新的二聚体表面分子，分子量为86，000，由43，000个糖肽亚基组成，不同于TcR异源二聚体、MHC Ⅱ类抗原和以前已知的T细胞二聚体蛋白。在一些T细胞克隆上也存在单体形式。蛋白质测序和基因克隆的方法正在进行中，I-J多肽在抗原识别后的T细胞早期信号转导中可能起着重要的调节作用。当用单克隆抗I-J ^k预处理具有I-J ^k表位的T细胞克隆时，由抗原脉冲的抗原呈递细胞随后刺激诱导的Ca^++内流被极大地抑制。抗TcR异源二聚体诱导的Ca^++反应同样被抗I β J抑制，而抗CD 3或Con A则无此作用。I-J分子被完整抗体连接而不是被Fab连接是启动抑制所必需的。抑制Ca^++内流的模式与用Ts克隆预孵育的Th克隆中观察到的非常相似。提示I-J受体的负性信号可抑制自身MHC反应性T细胞在个体发育和外周的扩增。少