Project Details
Projekt
T cell diversity and plasticity during pregnancy and their contribution to multiple sclerosis disease activity
Subject Area
Gynaecology and Obstetrics
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 255154572
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.
DFG Programme
Clinical Research Units
