The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/11/1597/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 9, November 3, 1997 1597-1602

Brief Definitive Reports

Inhibition of T Cell and Promotion of Natural Killer Cell Development by the Dominant Negative Helix Loop Helix Factor Id3

Mirjam H.M. Heemskerk*, Bianca Blom*, Garry Nolan{ddagger}, Alexander P.A. Stegmann*, Arjen Q. Bakker*, Kees Weijer*, Pieter C.M. Res*, and Hergen Spits*

From the * Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; and {ddagger} Department of Pharmacology, Stanford University, Palo Alto, California

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.

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: hergen{at}nki.nl


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