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

多发性硬化症(MS)是一种炎性、脱髓鞘的中枢神经系统疾病，被认为是由T细胞驱动的。在妊娠期，多发性硬化症患者的复发率大约降低了80%，而在产后前六个月，疾病活跃度增加了。然而，妊娠对疾病活动的这种戏剧性调节的潜在生物学机制却知之甚少。在KFO296的第一个资助期，我们观察到多发性硬化症的怀孕显著改变了T细胞的克隆组成，使其朝着更均匀分布的方向发展，这是由少数-主要是私人-T细胞克隆的选择性下调所驱动的。这表明，妊娠的免疫调节是非常特异的，为研究选择性耐受诱导的内源性机制提供了一个独特的窗口。此外，在实验性自身免疫性脑脊髓炎(EAE)的妊娠保护动物模型中，我们发现与妊娠相关的类固醇激素直接被T细胞感知，并通过与糖皮质激素受体的结合介导调节性T细胞的相对丰富，提供了一条可能的诱导特异性耐受的途径。在第二个资助期，我们旨在通过破译妊娠诱导T细胞分化、多样性和功能的分子机制，进一步推动对妊娠诱导T细胞反应影响MS病程的这些见解。除了我们成熟的EAE动物怀孕模型外，我们还将使用我们建立的机制研究方法，对目前可从我们的王子怀孕健康女性队列和附加的MS怀孕女性患者队列中获得的样本进行翻译，以解决三个具体目标：首先，我们将表征CD4T细胞分化的变化，认为这是MS/EAE怀孕免疫适应的推定驱动因素。其次，我们的目标是破译哪些细胞内程序对妊娠期间MS/EAE患者T细胞分化和活性的这种变化负责。最后，我们将使用条件性基因敲除动物模型和人类原始T细胞的体外实验，确定CD4分化过程中的关键分子靶点，这些靶点对于协调妊娠免疫适应是必要的和充分的。总之，这些研究有可能揭示怀孕期间高度特异的免疫调节的分子基础，这可能为针对与人类自身免疫相关的特定T细胞适应的上游调节以及移植和生殖医学等相关领域的新治疗方法提供信息。

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.