Development of therapy method target against OX40 signal for allergy or autoimmune diseases

开发针对过敏或自身免疫性疾病的 OX40 信号靶点的治疗方法

基本信息

批准号：
17607001
负责人：
MURATA Kazuko
金额：
$ 2.3万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17607001/
关键词：
Autoimmunity Co-stimulatory molecule

项目摘要

Signals through the OX40 costimulatory receptor on naive CD4 T cells are essential for full-fledged CD4 T cell activation and the generation of CD4 memory T cells. Because the ligand for OX40 is mainly expressed by APCs, including activated B cells, dendritic cells, and Langerhans cells, the OX40-0X40 ligand (OX40L) interaction has been thought to participate in T cell-APC interactions. Although several reports have revealed the expression of OX40L on T cells, the functional significance of its expression on them is still unclear. In this study, we demonstrate that Ag stimulation induced an increase in the surface expression and transcript levels of OX40L in CD4 T cells. Upon contact with OX40-expressing T cells, the cell surface expression of OX40L on CD4 T cells was markedly down-regulated, suggesting that OX40-OX40L binding occurs through a novel T cell-T cell interaction. To investigate the function of this phenomenon, we examined the proliferative response and survival of OX40L-deficient CD4 T cells when challenged with Ag. In vitro studies demonstrated markedly less CD3-induced proliferation of OX40L-deficient CD4 T cells compared with wild-type CD4 T cells. When using TCR transgenic CD4 T cells upon Ag stimulation, survival of OX40L-deficient T cells was impaired. Furthermore, we show that upon antigenic stimulation, fewer OX40L-deficient CD4 T cells than wild-type cells survived following transfer into wild-type and sublethally irradiated recipient mice. Taken together, our findings indicate that OX40L-expressing T cells have an autonomous machinery that provides OX40 signals through a T cell-T cell circuit, creating an additional mechanism for sustaining CD4 T cell longevity.

通过OX40 COTULATION受体在幼稚CD4 T细胞上的信号对于成熟的CD4 T细胞激活和CD4记忆T细胞的产生至关重要。由于OX40的配体主要由APC表达，包括活化的B细胞，树突状细胞和Langerhans细胞，因此人们认为OX40-0X40配体（OX40L）相互作用被认为参与T细胞-APC相互作用。尽管有几份报道揭示了OX40L在T细胞上的表达，但其表达在其上的功能意义尚不清楚。在这项研究中，我们证明AG刺激会引起CD4 T细胞中OX40L的表面表达和转录水平的增加。与表达OX40的T细胞接触后，CD4 T细胞上OX40L的细胞表面表达明显下调，这表明OX40-OX40L结合通过新型T细胞-T细胞相互作用发生。为了研究这种现象的功能，我们检查了在用Ag挑战时OX40L缺乏的CD4 T细胞的增殖反应和存活。体外研究表明，与野生型CD4 T细胞相比，CD3诱导的OX40L缺陷CD4 T细胞的增殖明显较少。当使用TCR转基因CD4 T细胞Ag刺激时，OX40L缺陷T细胞的存活受损。此外，我们表明，在抗原刺激下，与野生型细胞相比，在转移到野生型和共辐照的受体小鼠中，OX40L缺陷的CD4 T细胞少于野生型细胞。综上所述，我们的发现表明，表达OX40L的T细胞具有通过T Cell-T细胞电路提供OX40信号的自主机制，从而创造了一种维持CD4 T细胞寿命的附加机制。