B15 – Andreas Krueger

Molecular mechanisms of T-cell regeneration by miRNAs after stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is applied as therapy for a number of malignant and non-malignant diseases mostly of the hematopoietic system. However, HSCT is generally accompanied with a prolonged phase of immunodeficiency resulting from slow recovery of the T cell arm of the adaptive immune system, the consequences of which are reduced control of opportunistic infections as well as an increased risk of malignant relapse. Developing strategies to improve T lineage reconstitution after HSCT depends on a thorough understanding of the mechanisms governing hematopoietic lineage decisions. Such lineage decisions occur as progressive loss of alternate lineage fates as well as loss of self-renewal potential of hematopoietic stem cells. They are induced by both instructive events, such as extrinsic signals, and stochastic events, such as fluctuations in expression of lineage-specific transcription factors. The role of miRNAs in these decisions remains ill understood. We have previously investigated the interdependence of transcription factor controlled gene regulatory programs and miRNAs downstream of these programs. We have identified 2 families of miRNAs, miR-17~92 and miR-181, with profound impact on T cell development and, thus, with the potential to serve as candidate targets to develop strategies for improved T lineage regeneration. However, our understanding of the role of miRNAs suffers from the complex biology of miRNA-mediated gene regulation. Thus, miRNAs frequently target hundreds of potentially relevant genes, many of which are modulated to a small extent only. Consequently, it remains a difficult but equally important task to identify functionally relevant miRNA targets. In order to be able to translate findings from murine models into strategies for improved T lineage regeneration robust and flexible experimental tools to study human T cell differentiation are required. However, to date in vitro models rely on primary cells with limited availability and humanized mouse models do not reliably recapitulate the human system. Here we will dissect miRNA-mRNA target relationships relevant for both physiological T cell development and T lineage regeneration after HSCT. The proposed project will provide important insight into the integration of miRNAs in gene regulatory networks governing physiological T cell development and T lineage regeneration after HSCT in both mouse and human. Furthermore, the technological advances envisioned for the project are likely to impact future studies of miRNA biology and hematopoiesis in general.

Team

Andreas Krueger (Principal Investigator)
 
Balasai Sundarasetty
 
Samantha Winter
 
Esther Imelmann