Project Details
Projekt
Deciphering the organ-specific CD8+ T cell receptor and cognate epitope repertoire in graft-versus-host disease
Applicant
Dr. Maren Schmiester
Subject Area
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517286481
Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for life-threatening hematological diseases. Graft-versus-host disease (GvHD), however, where donor T cells recognize antigens expressed by healthy host cells as foreign and mount tissue-destructive immune responses, remains a key adverse event. There is a pressing clinical need to advance the pathogenetic understanding of the disease and to develop new strategies in order to improve clinical outcomes. Alloreactive T cells are the chief drivers of acute GvHD, carrying out cell-mediated immune responses upon engagement of their specific T cell receptor (TCR) with complexes of cognate antigens and their presenting major histocompatibility complex (MHC) molecules. In addition to mismatched host antigens able to trigger T cell activation, the gut microbiome is known to impact the development of alloreactivity after HSCT, even contributing to mortality. Novel technologies for TCR sequencing have shed light on TCR repertoire composition after HSCT, but the other half of the picture, i.e., the cognate antigens of those TCRs, has been difficult to study due to technical limitations until now. The host laboratory has recently developed a high-throughput, cell-based TCR antigen screening platform that allows for the identification of specific epitopes of TCRs of interest from a cDNA library. The overarching goal of this project is to improve upon the current pathogenetic understanding of GvHD by deciphering the organ-specific CD8+ TCR and cognate epitope repertoire after murine HSCT and by delineating the impact of dysbiosis on the intestinal TCR repertoire and its antigen specificities. Using a well-described mouse model for HSCT with and without a modified microbiome, single-cell TCR sequencing of lymphoid and parenchymatous organs, histological analyses and microbiome profiling, I will characterize the organ-specific TCR repertoire in GvHD and analyze the influence of gut commensals on its composition. With the novel approach to TCR antigen discovery, I will then systematically identify cognate host and microbial antigens driving immune responses of CD8+ T cells in GvHD. Findings will contribute to the understanding of CD8+-mediated alloreactivity in GvHD and provide a comprehensive depiction of the antigens shaping CD8+ allorecognition. These pathogenetic insights can in turn contribute to the development of new diagnostic and therapeutic approaches.
DFG Programme
WBP Fellowship
International Connection
USA
