Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3.
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.
Heemskerk
M H
MH
Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Blom
B
B
Nolan
G
G
Stegmann
A P
AP
Bakker
A Q
AQ
Weijer
K
K
Res
P C
PC
Spits
H
H
D000818:Animals; D018949:Antigens, CD1 / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002648:Child; D005333:Fetus; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000187:drug effects; D006131:Growth Inhibitors / Q000502:physiology*; D018257:Helix-Loop-Helix Motifs / Q000276:immunology* / Q000502:physiology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins; D015851:Interleukin-7 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins; D009924:Organ Culture Techniques; D019089:Stem Cell Factor / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*
D018949:Antigens, CD1; D018952:Antigens, CD34; D006131:Growth Inhibitors; D051796:Inhibitor of Differentiation Proteins; D015851:Interleukin-7; D009363:Neoplasm Proteins; D019089:Stem Cell Factor; D014157:Transcription Factors; C075640:ID3 protein, human