INHIBITION OF T-CELL AND PROMOTION OF NATURAL-KILLER-CELL DEVELOPMENTBY 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 de velop predominantly to T cells in the thymus. The mechanisms controlli ng this developmental choice are unknown. Here we present evidence tha t a member(s) oi the family of basic helix loop helix (bHLH) transcrip tion factors determines lineage specification of NWT cell progenitors. The natural dominant negative HLH factor Id3, which blocks transcript ional activity of a number of known bHLH factors, was expressed in CD3 4(+) progenitor cells by retrovirus-mediated gene transfer. Constituti ve expression of Id3 completely blocks development of CD34(+) cells in to T cells in a fetal thymic organ culture (FTOC). In contrast, develo pment into NK cells in an FTOC is enhanced. Thus, the activity of a bH LH transcription factor is necessary for T lineage differentiation of bipotential precursors, in the absence of which a default pathway lead ing to NK call development is chosen. Our results identify a molecular -switch for lineage specification in early lymphoid precursors of huma ns.