Details

Autor(en) / Beteiligte

• Taghon, Tom N
• Liang, Kai Ling
• Lavaert, Marieke
• Roels, Juliette
• Strubbe, Steven
• Lambrechts, Nina
• De Vos, Tamara
• Boehme, Lena
• Van Hulle, Jolien
• Oatman, Nicole
• Putteman, Tom
• Velghe, Imke

Titel

An unexpected role for IRF8 during human T cell development

Ist Teil von

• The Journal of immunology (1950), 2022-05, Vol.208 (1_Supplement), p.107-107.06

Erscheinungsjahr

2022

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract Lineage tracing studies or other genetic approaches have allowed investigators to obtain detailed insights into the molecular mechanisms that control T cell development in the mouse. However, our understanding of how this process is regulated in human has remained unclear. Using various genome-wide approaches, such as bulk RNAseq, ATACseq, ChIPseq and scRNAseq, we have recently obtained important novel insights into the molecular mechanisms through which human hematopoietic progenitor cells are converted into T-lineage committed precursors, and further into the TCRαβ and −γδ lineages. Specifically, we identified two distinct populations of thymus seeding precursor cells (TSPs) of which one population, TSP2, expressed IRF8, a transcription factor that is mainly associated with dendritic cell development. Consistently, IRF8-expressing TSPs have both T− and DC-linage potential and are characterised by the coexpression of CD127 and CD123. We discovered that Notch activation, the main initiator of T-lineage specification, induces IRF8 expression in human ETPs, in contrast to in mouse, and that IRF8 is transiently expressed during early human T cell development. As T cell precursors commit to the T-cell lineage, IRF8 is repressed by GATA3, while IRF8 levels rise for ETPs that differentiate into plasmacytoid dendritic cells. Importantly, IRF8 is required for the generation of CD34+ CD127+ CD123+ T/DC precursors and low level IRF8 activity enhances their generation from hematopoietic progenitors. Thus, using these approaches, we have identified an IRF8-dependent T cell precursor subset and revealed unique molecular events that control early T cell development in human. Supported by grants from the Fund for Scientific Research Flanders (FWO), the Foundation Against Cancer (STK), the Chan Zuckerberg Initiative (CZI) and Ghent University (BOF Ugent).