T cell diversity and plasticity during pregnancy and their contribution to multiple sclerosis disease activity

多发性硬化症（MS）是一种中枢神经系统的炎性脱髓鞘疾病，被认为是T细胞驱动的。在怀孕期间，MS患者显示复发率降低约80%，而在产后前六个月，疾病活动增加。然而，对妊娠对疾病活动的这种戏剧性调节的潜在生物学机制知之甚少。在KFO 296的第一个资助期内，我们观察到MS中的妊娠显著改变了T细胞的克隆组成，使其分布更均匀，这是由少数-主要是私人- T细胞克隆的选择性下调驱动的。这表明，免疫调节怀孕是非常具体的，提供了一个独特的窗口选择性耐受诱导内源性机制。此外，在预防MS（实验性自身免疫性脑脊髓炎，EAE）的妊娠保护动物模型中，我们发现妊娠相关的类固醇激素直接被T细胞感知，并通过糖皮质激素受体的参与介导调节性T细胞的相对富集，提供了一个推定的途径，通过该途径可以诱导特异性耐受。在第二个资助期，我们的目标是通过破译控制妊娠诱导的T细胞分化，多样性和功能的分子机制，进一步推进这些关于妊娠诱导的T细胞反应影响MS过程的见解。除了我们完善的EAE动物妊娠模型外，我们还使用我们已建立的机制研究的转化方法，对来自我们的PRINCE妊娠健康女性队列和MS妊娠女性患者的附加队列的样本进行研究，我们将解决三个具体目标：首先，我们将确认CD 4 T细胞分化的变化是MS/EAE中妊娠免疫适应的假定驱动因素。第二，我们的目标是破译细胞内程序负责这种变化，T细胞分化和活动在MS/EAE妊娠期间。最后，我们将确定关键的分子靶点内的CD 4分化过程中，是必要的和足够的协调免疫适应妊娠使用条件性基因敲除动物模型和体外实验与人的初级T细胞。总之，这些研究有可能揭示妊娠期间高度特异性免疫调节的分子基础，这可以为靶向与人类自身免疫相关的特定T细胞适应的上游调节因子以及移植和生殖医学等相关领域提供新的治疗方法。

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system that is thought to be T cell-driven. During pregnancy, MS patients show an approximately 80% reduction in relapse rates, while in the first six months post partum disease activity is increased. However, the underlying biological mechanisms for this dramatic modulation of disease activity by pregnancy are, poorly understood. During the first funding period of KFO296, we observed that pregnancy in MS significantly alters clonal composition of T cells towards a more evenly distributed repertoire, driven by selective downregulation of a few – largely private – T cell clones. This suggests that immunomodulation by pregnancy is remarkably specific, providing a unique window into endogenous mechanisms of selective tolerance induction. Moreover, in the animal model of pregnancy protection from MS (experimental autoimmune encephalomyelitis, EAE), we discovered that pregnancy-related steroid hormones are directly sensed by T cells and mediate a relative enrichment of regulatory T cells via engagement of the glucocorticoid receptor, providing a putative pathway by which specific tolerance could be induced. In the second funding period, we aim at further advancing these insights on pregnancy-induced T cell responses affecting the course of MS by deciphering the molecular mechanisms governing pregnancy-induced T cell differentiation, diversity and function. Using our established translational approach of mechanistic studies in samples now available from our PRINCE cohort of pregnant healthy women and add-on cohort of pregnant female patients with MS in addition to our well-established EAE animal pregnancy model, we will address three specific aims: First, we will characterise shifts in CD4 T cell differentiation as a putative driver of immune adaptation to pregnancy in MS/EAE. Second, we aim to decipher which intracellular programs are responsible for this change in T cell differentiation and activity during pregnancy in MS/EAE. Finally, we will identify key molecular targets within the CD4 differentiation process that are necessary and sufficient to orchestrate immune adaptation to pregnancy using conditional knock-out animal models and in vitro experiments with human primary T cells. Together, these studies have the potential to uncover the molecular underpinnings of highly specific immunomodulation during pregnancy, which could inform novel treatment approaches that target upstream regulators of specific T cell adaptation with relevance to human autoimmunity as well as related fields such as transplantation and reproductive medicine.