权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Conversion of anergic non-regulatory into Foxp3- IL-10+ regulatory T cells by dendritic cells in vivo

体内树突状细胞将无能非调节性 T 细胞转化为 Foxp3-IL-10 调节性 T 细胞

基本信息

批准号：
338949849
负责人：
Professor Dr. Manfred Lutz
金额：
--
依托单位：
Institut für Virologie und Immunbiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/338949849?language=en
关键词：
Conversion anergic non regulatory into

项目摘要

T cell anergy is a long known mechanism of T cell tolerance. However, it remains unclear why such T cells with unwanted T cell reactivity are not eliminated, since their passive persistence bears the potential risk of reactivation. We have shown before in vitro that anergic T cells can be converted by immature dendritic cells (DCs) into Foxp3- IL-10+ regulatory T cells (Tr1). Surprisingly, the expression of both CD28 and CTLA-4 molecules was functionally required for this process. Since the expression of CTLA-4 is only transient the anergy-to-Tr1 conversion can occur only in a small time window. This proposal aims to show that anergy-to-Tr1 conversion can occur in vivo in the spleen and requires CD28 and CTLA-4 expression by the anergic T cells. Inducible deletion of either molecule in T cell receptor (TCR)-transgenic T cells will give clear answers to this questions. The use of gene-deficient mice with deletions of DC subset-specific transcription factors will allow to determine the contribution of CD8a+ or CD11b+ conventional DCs or plasmacytoid DCs in anergy induction and anergy-to-Tr1 conversion. Furthermore, we want to demonstrate that in vivo persistent anergic T cells can serve as a reservoir pool of memory T cells awaiting their reactivation into Tr1 cells. Adapted protocols resulting from this knowledge will then be used to suppress experimental autoimmune-encephalomyelitis (EAE) and asthma in mice. Our preliminary data indicate that high antigen doses as used for anergy induction and anergy-to-Tr1 conversion may override the availability of TGF-b to induce Foxp3+ inducible regulatory T cells (iTreg) as we have shown before by implanting osmotic minipumps in mice to deliver low doses of antigen. This question will be addressed by transfer of TCR-transgenic T cells with defective TGF-b receptor or reversely, by injecting high doses of TGF-b into mice with TGF-b receptor competent T cells during anergy induction or anergy-to-Tr1 conversion.Together, the proposed experiments will allow to attribute an active immunological role in T cell tolerance to anergic T cells in vivo as well as the functional role of CD28, CTLA-4 and TGF-b in the anergy-to-Tr1 conversion process and to identify the participating DC subsets.

T细胞无反应性是T细胞耐受性的长期已知机制。然而，目前尚不清楚为什么这些具有不需要的T细胞反应性的T细胞没有被消除，因为它们的被动持久性具有重新激活的潜在风险。我们之前已经在体外证明，无反应性T细胞可以被未成熟树突状细胞（DC）转化为Foxp 3- IL-10+调节性T细胞（Tr 1）。令人惊讶的是，CD 28和CTLA-4分子的表达在功能上是该过程所需的。由于CTLA-4的表达仅是短暂的，因此Anergy至Tr 1的转化仅能在小的时间窗内发生。该提议旨在表明无反应性T细胞在体内可在脾脏中发生无反应性向Tr 1的转化，并且需要CD 28和CTLA-4表达。在T细胞受体（TCR）转基因T细胞中诱导缺失任何一种分子将为这个问题提供明确的答案。使用缺失DC亚群特异性转录因子的基因缺陷小鼠将能够确定CD 8a+或CD 11b+常规DC或浆细胞样DC在无反应性诱导和无反应性向Tr 1转化中的贡献。此外，我们想证明，在体内持续性无反应性T细胞可以作为一个水库池的记忆T细胞等待他们重新激活成Tr 1细胞。从这方面的知识所产生的适应协议，然后将用于抑制实验性自身免疫性脑脊髓炎（EAE）和哮喘小鼠。我们的初步数据表明，用于无反应性诱导和无反应性转化为Tr 1的高抗原剂量可能会超过TGF-β诱导Foxp 3+诱导型调节性T细胞（iTreg）的可用性，正如我们之前通过在小鼠中植入渗透微型泵以递送低剂量抗原所显示的那样。这个问题将通过转移具有缺陷的TGF-b受体或CD 28的TCR转基因T细胞，通过在无反应诱导或无反应转化为Tr 1期间将高剂量的TGF-b注射到具有TGF-b受体感受态T细胞的小鼠中来解决。CTLA-4和TGF-b在Anergy-to-Tr 1转换过程中的作用，并确定参与DC亚群。