RBPJ-dependent Notch signaling initiates the T cell program in a subset of thymus-seeding progenitors

Abstract

T cell specification and commitment requires Notch signaling. Although the requirement for Notch signaling during intrathymic T cell development is known, it is still unclear whether the onset of T cell priming can occur in a pre-thymic niche and whether RBPJ-dependent Notch signaling has a role during this event. Here we established an Rbpj-inducible system that allowed the temporal and tissue-specific control of the responsiveness to Notch in all hematopoietic cells. Using this system, we found that Notch signaling was required prior to the early T cell progenitor stage in the thymus. Lymphoid-primed multipotent progenitors in the bone marrow underwent Notch signaling with Rbpj induction, which inhibited development towards the myeloid lineage in thymus-seeding progenitors. Thus, our results indicated that the onset of T cell differentiation occurred in a pre-thymic setting, and that Notch played an important role during this event.

Single cell profiling of immature human postnatal thymocytes resolves the complexity of intra-thymic lineage differentiation and thymus seeding precursors

“…Also their topology within the thymus suggests that these TSP1s represent the canonical T cell precursors that differentiate into ETPs when they encounter Notch activating signals within the thymic microenvironment. And while TSP1s themselves do not display any signs of Notch activation, we also identified a lin -CD34 + CD44 hi CD7 int CD10seeding population which resembles the Notch-primed TSPs that have been described in the BM of mice (Chen et al, 2019;Yu et al, 2015) . This TSP2 population indeed expresses the Notch target genes CD7 and CD3E prior to thymic entry, consistent with these studies.…”

The transcriptional repressor Bcl6 promotes pre-TCR induced differentiation to CD4+CD8+ thymocyte and attenuates Notch1 activation

“…We therefore compared expression of Notch-associated DEG from DP datasets, and found increased expression of many genes upregulated by Notch signalling in the Bcl6coKO compared to control, and decreased expression of genes that are downregulated by Notch activation in thymocytes (Arenzana et al, 2015;Chen et al, 2019) ( Figure 4A). Consequently, to test on a wider set of genes if conditional deletion of Bcl6 led to an overall increase in Notch-mediated transcription, we carried out CCA to compare our DP datasets to the transcriptome of control thymocytes and those with enhanced Notch1-mediated transcription (Arenzana et al, 2015).…”

Specific Targeting of Notch Ligand-Receptor Interactions to Modulate Immune Responses: A Review of Clinical and Preclinical Findings

“…This results increased apoptosis of TECs, dysregulated lineage-commitment checkpoints, diminished TCR repertoire and low thymic output, all of which ultimately dampen immunosurveillance and promote tumor escape. In immature DN2 T cell subsets, CCR7 is a target of Notch1 and is important for the migration of developing T cell precursors through the thymic cortex to medulla ( 102 – 104 ). Reduction in expression levels of Notch1 and its targets in thymic pre-T cells of tumor-bearing mice is mediated by IL-10 produced by thymic epithelial cells (TECs) ( 45 ).…”