1001 – HOW T LYMPHOID CELL IDENTITY EMERGES FROM HEMATOPOIETIC MOLECULAR MECHANISMS

Abstract

T lymphocytes are not just antigen-recognizing immunologic units. They are notable products of hematopoietic differentiation that combine aspects of highly active effectors with sustained stemness. They have high gene regulatory responsiveness, yet retain exceptionally long-term capacities to proliferate and self-renew, although sustaining a unique core of gene expression that defines their identity as T cells. The ways they manage their exponential amplification potential are instructive as examples to restrain leukemogenesis. They acquire all these properties outside of the bone marrow, during passage through the thymus. The thymus enables this process by delivering strong Notch pathway signals to multipotent hematopoietic precursors until they relinquish alternative potentials and undergo commitment to the T-cell lineage.

This talk focused on the way the T-cell program emerges from a lymphomyeloid precursor epigenetic and transcriptional regulatory state. The separation of the precursors from the bone marrow and the availability of powerful in vitro culture systems to mimic the thymus have enabled a deep molecular analysis of the underlying mechanisms. Although Notch signaling acts as a catalyst, it is the cell-intrinsic regulatory features that give this widely used signal its specific T-cell program impacts. One key feature is the ensemble of factors that guide T-cell development, which lack a distinctive “master regulator.” All are identical or closely related to transcription factors used in other hematopoietic fates but are pivoted through collaboration to special roles in the T-cell program. A second key feature is the prolonged use of a multipotent progenitor gene regulatory network circuit to set the foundation for activation of the T-cell program. This involves the same regulatory genes that can act as oncogenes if not completely and accurately silenced. Their activity means that T-cell development begins with a competition between two partially opposing gene network circuits within individual cell nuclei that is resolved only when the cells undergo commitment.

T lymphocytes are not just antigen-recognizing immunologic units. They are notable products of hematopoietic differentiation that combine aspects of highly active effectors with sustained stemness. They have high gene regulatory responsiveness, yet retain exceptionally long-term capacities to proliferate and self-renew, although sustaining a unique core of gene expression that defines their identity as T cells. The ways they manage their exponential amplification potential are instructive as examples to restrain leukemogenesis. They acquire all these properties outside of the bone marrow, during passage through the thymus. The thymus enables this process by delivering strong Notch pathway signals to multipotent hematopoietic precursors until they relinquish alternative potentials and undergo commitment to the T-cell lineage.

This talk focused on the way the T-cell program emerges from a lymphomyeloid precursor epigenetic and transcriptional regulatory state. The separation of the precursors from the bone marrow and the availability of powerful in vitro culture systems to mimic the thymus have enabled a deep molecular analysis of the underlying mechanisms. Although Notch signaling acts as a catalyst, it is the cell-intrinsic regulatory features that give this widely used signal its specific T-cell program impacts. One key feature is the ensemble of factors that guide T-cell development, which lack a distinctive “master regulator.” All are identical or closely related to transcription factors used in other hematopoietic fates but are pivoted through collaboration to special roles in the T-cell program. A second key feature is the prolonged use of a multipotent progenitor gene regulatory network circuit to set the foundation for activation of the T-cell program. This involves the same regulatory genes that can act as oncogenes if not completely and accurately silenced. Their activity means that T-cell development begins with a competition between two partially opposing gene network circuits within individual cell nuclei that is resolved only when the cells undergo commitment.