The role of CD28-mediated signals in programming and reprogramming of mouse and human memory and induced regulatory T cells

CD28介导的信号在小鼠和人类记忆编程和重编程以及诱导调节性T细胞中的作用

• 批准号: 245011612
• 负责人: Privatdozent Dr. Niklas Beyersdorf, since 10/2017
• 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: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245011612?language=en
• 关键词: role; CD28; mediated; signals; programming

Upon appropriate stimulation, naive T cells express certain transcription factors such as T-bet or Gata-3 which guide their differentiation into functionally polarised complementary effector/memory populations. These cells belonging to the Th1, Th2 or to the more recently identified Th17 lineages are then thought to cross-regulate each other. However, there is now a substantial body of evidence for lineage plasticity meaning that e.g. Th2 cells may also acquire properties of Th1 cells. While the role of CD28-mediated co-stimulation is well documented during primary differentiation of naive T cells into effector/memory cells, the impact of CD28 stimulation on the reprogramming of effector and memory T cells is so far largely unknown. Moreover, induced Foxp3+ regulatory T cells, which bear great therapeutic potential, also display a high degree of plasticity in vivo depending on the disease model studied. In the experiments proposed herein we would, therefore, like to address the impact of CD28 stimulation on the reprogramming of fully differentiated mouse and human T cells in greater detail. To this end we will not only use CD28-specific reagents blocking ligand binding but also the novel inducible CD28-deleter mouse strain CD28-/flox, rosa(CreERT2) (iCD28k.o.) to study T cell reprogramming in vitro and during antigen-driven immune responses in vivo. We believe that the scheduled experiments will not only provide deeper insights into T cell differentiation in general but will also help to develop novel therapeutic strategies for humans who, in contrast to cleanly housed laboratory mice, contain large populations of fully differentiated memory T cells.

在适当的刺激下，幼稚T细胞表达某些转录因子，如T-bet或GATA-3，这些转录因子引导它们分化为功能极化的互补效应/记忆群体。然后，这些属于Th1、Th2或最近发现的Th17谱系的细胞被认为相互交叉调节。然而，现在有大量证据表明谱系可塑性，这意味着例如Th2细胞也可能获得Th1细胞的特性。虽然CD28介导的共刺激在初始T细胞分化为效应/记忆细胞过程中的作用得到了很好的证实，但CD28刺激对效应T细胞和记忆T细胞重新编程的影响迄今尚不清楚。此外，诱导的Foxp3+调节性T细胞具有巨大的治疗潜力，在体内也表现出高度的可塑性，这取决于所研究的疾病模型。因此，在这里提出的实验中，我们想更详细地讨论CD28刺激对完全分化的小鼠和人类T细胞重新编程的影响。为此，我们不仅将使用CD28特异性试剂来阻断配体结合，而且还将使用可诱导的CD28-/FLOX新品系ROSA(CreERT2)(iCD28k.o.)目的：研究T细胞在体外和体内抗原诱导免疫应答过程中的重编程。我们相信，预定的实验不仅将提供对T细胞分化的一般更深入的见解，还将有助于为人类开发新的治疗策略，与干净的实验室小鼠相比，人类拥有大量完全分化的记忆T细胞。