Bipotential T/natural killer (NK) progenitor cells are present in the human thymus. Despite their bipotential capacity, these progenitors develop predominantly to T cells in the thymus. The mechanisms controlling this developmental choice are unknown. Here we present evidence that a member(s) of the family of basic helix loop helix (bHLH) transcription factors determines lineage specification of NK/T cell progenitors. The natural dominant negative HLH factor Id3, which blocks transcriptional activity of a number of known bHLH factors, was expressed in CD34+ progenitor cells by retrovirus-mediated gene transfer. Constitutive expression of Id3 completely blocks development of CD34+ cells into T cells in a fetal thymic organ culture (FTOC). In contrast, development into NK cells in an FTOC is enhanced. Thus, the activity of a bHLH transcription factor is necessary for T lineage differentiation of bipotential precursors, in the absence of which a default pathway leading to NK cell development is chosen. Our results identify a molecular switch for lineage specification in early lymphoid precursors of humans.
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3 November 1997
Brief Definitive Report|
November 03 1997
Inhibition of T Cell and Promotion of Natural Killer Cell Development by the Dominant Negative Helix Loop Helix Factor Id3
Mirjam H.M. Heemskerk,
Mirjam H.M. Heemskerk
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
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Bianca Blom,
Bianca Blom
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
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Garry Nolan,
Garry Nolan
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
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Alexander P.A. Stegmann,
Alexander P.A. Stegmann
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
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Arjen Q. Bakker,
Arjen Q. Bakker
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
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Kees Weijer,
Kees Weijer
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
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Pieter C.M. Res,
Pieter C.M. Res
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
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Hergen Spits
Hergen Spits
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
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Mirjam H.M. Heemskerk
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
Bianca Blom
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
Garry Nolan
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
Alexander P.A. Stegmann
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
Arjen Q. Bakker
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
Kees Weijer
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
Pieter C.M. Res
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
Hergen Spits
From the *Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and ‡Department of Pharmacology, Stanford University, Palo Alto, California
Address correspondence to Dr. Hergen Spits, Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Phone: 31-20-5122063; FAX: 31-20-5122057; E-mail: [email protected]
Received:
July 07 1997
Revision Received:
August 21 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 186 (9): 1597–1602.
Article history
Received:
July 07 1997
Revision Received:
August 21 1997
Citation
Mirjam H.M. Heemskerk, Bianca Blom, Garry Nolan, Alexander P.A. Stegmann, Arjen Q. Bakker, Kees Weijer, Pieter C.M. Res, Hergen Spits; Inhibition of T Cell and Promotion of Natural Killer Cell Development by the Dominant Negative Helix Loop Helix Factor Id3 . J Exp Med 3 November 1997; 186 (9): 1597–1602. doi: https://doi.org/10.1084/jem.186.9.1597
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