The role of CD28-mediated signals in programming and reprogramming of mouse and human memory and induced regulatory 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，这些转录因子指导它们分化成功能极化的互补效应/记忆群体。这些细胞属于Th1， Th2或最近发现的Th17谱系，然后被认为是相互交叉调节的。然而，现在有大量证据表明谱系可塑性，这意味着Th2细胞也可能获得Th1细胞的特性。虽然CD28介导的共刺激在幼稚T细胞向效应/记忆细胞的初代分化过程中的作用已经得到了充分的证明，但CD28刺激对效应和记忆T细胞重编程的影响迄今为止在很大程度上是未知的。此外，诱导的Foxp3+调节性T细胞具有很大的治疗潜力，根据所研究的疾病模型，在体内也表现出高度的可塑性。因此，在本文提出的实验中，我们希望更详细地解决CD28刺激对完全分化的小鼠和人类T细胞重编程的影响。为此，我们不仅将使用CD28特异性试剂阻断配体结合，还将使用新型诱导CD28缺失小鼠品系CD28-/flox， rosa(CreERT2) （iCD28k.o.）在体外和体内抗原驱动免疫反应中研究T细胞重编程。我们相信，计划中的实验不仅将提供对T细胞分化的更深入的了解，而且还将有助于为人类开发新的治疗策略，与清洁饲养的实验室小鼠相比，人类含有大量完全分化的记忆T细胞。

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.