title: HEB-deficient T-cell precursors lose T-cell potential and adopt an alternative pathway of differentiation.
abstract: Early thymocytes possess multilineage potential, which is progressively restricted as cells transit through the double-negative stages of T-cell development. DN1 cells retain the ability to become natural killer cells, dendritic cells, B cells, and myeloid cells as well as T cells, but these options are lost by the DN3 stage. The Notch1 signaling pathway is indispensable for initiation of the T-cell lineage and inhibitory for the B-cell lineage, but the regulatory mechanisms by which the T-cell fate is locked in are largely undefined. Previously, we discovered that the E-protein transcription factor HEBAlt promoted T-cell specification. Here, we report that HEB(-/-) T-cell precursors have compromised Notch1 function and lose T-cell potential. Moreover, reconstituting HEB(-/-) precursors with Notch1 activity enforced fidelity to the T-cell fate. However, instead of becoming B cells, HEB(-/-) DN3 cells adopted a DN1-like phenotype and could be induced to differentiate into thymic NK cells. HEB(-/-) DN1-like cells retained GATA3 and Id2 expression but had lower levels of the Bcl11b gene, a Notch target gene. Therefore, our studies have revealed a new set of interactions between HEB, Notch1, and GATA3 that regulate the T-cell fate choice in developing thymocytes.
authors.affiliation: Sunnybrook Research Institute and Department of Immunology, University of Toronto, 2075 Bayview Ave., Toronto, Ontario, Canada.
authors.forename: Marsela
authors.initials: M
authors.lastname: Braunstein
authors.forename: Michele K
authors.initials: MK
authors.lastname: Anderson
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D050990:GATA3 Transcription Factor / Q000032:analysis / Q000378:metabolism*; D051797:Inhibitor of Differentiation Protein 2 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology / Q000502:physiology*; D051881:Receptor, Notch1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050990:GATA3 Transcription Factor; D051797:Inhibitor of Differentiation Protein 2; D051881:Receptor, Notch1; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C511143:Bcl11b protein, mouse; C494748:Gata3 protein, mouse; C497452:Idb2 protein, mouse; C497762:Notch1 protein, mouse; C489532:Tcf12 protein, mouse