Epigenetic and transcriptional regulation of T cells

The successful outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) depends on the complete reconstitution of the host`s immune system by donor-derived T cells. However, the success of allo-HSCT is compromised by the development of complications such as graft-vs.-host- disease (GVHD), which remains a major cause of morbidity and mortality after hematopoietic stem cell transplantation (allo-HSCT), occurring after 30-40% of transplants and accounting for up to 15% of deaths. Acute GVHD is characterized by host tissue injury, mediated by donor T cells following interaction with either donor- or host-derived antigen presenting cells (APCs). The interaction between APCs and donor T cells leads to changes in abundance and function of transcription factors, which in turn stimulate or repress expression of genes crucial for T cell recovery, responses and aGVHD. Epigenetic changes are thought to be important in regulation of gene expression in the course of T cell recovery and restoration of homeostatic conditions or manifestation of aGVHD, but it remains largely unknown how epigenetic processes and transcription factor activities regulate these processes by affecting the transcription of genes. Our preliminary results of the epigenetic signature of isolated T cells suggest differential transcriptional reprogramming in peripheral blood and skin T cells at different post transplantation time points (at day +14 and day +100). Since our preliminary findings based on bulk sequencing data suggest distinct transcriptional programs to modulate T cell recovery at different time points after transplantation, we hypothesize that T cells in different states after HSCT are poised for the development of acute/chronic GVHD. The objective of this study is to investigate the epigenetic and transcriptional changes which occur after transplantation at single cell resolution by various sequencing methods, and to identify key epigenetic regulators that contribute in the recovery of d istinct T cell populations at different pace and the restoration of homeostasis of host T cell repertoire. The second objective is to establish a time and cost-effective multi-omics based computational framework to study the underlying molecular mechanisms of stem cell transplanted patients to observe and improve the recovery of immune cells with low-input sequencing strategies.