title: T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1.
abstract: Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBP-α restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid cells and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: De Obaldia
authors.forename: J Jeremiah
authors.initials: JJ
authors.lastname: Bell
authors.forename: Xinxin
authors.initials: X
authors.lastname: Wang
authors.forename: Christelle
authors.initials: C
authors.lastname: Harly
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yashiro-Ohtani
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: DeLong
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Zlotoff
authors.forename: Dil Afroz
authors.initials: DA
authors.lastname: Sultana
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.forename: Avinash
authors.initials: A
authors.lastname: Bhandoola
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D022763:CCAAT-Enhancer-Binding Protein-alpha; D016207:Cytokines; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse