Commitment to natural killer cells requires the helix-loop-helix inhibitorId2

We have previously described how T and natural killer(NK) lineage commitmen t proceeds from common T/NK progenitors (p-T/NK) in the murine fetal thymus (FT), with the use of a clonal assay system capable of discriminating p-T/ NK from unipotent T or NK lineage-committed progenitors (p-T and p-NK, resp ectively). The molecular mechanisms controlling the commitment processes, h owever, are yet to be defined. In this study, we investigated the progenito r activity of FT cells from Id2(-/-) mice that exhibit defective NK cell de velopment. In the Id2(-/-) FT, NK cells were greatly reduced, and a cell po pulation that exclusively contains p-NK in the wild-type thymus was complet ely missing. Id2(-/-) FT progenitors were unable to differentiate into NK c ells in IL-2-supplemented-FT organ culture. Single progenitor analysis demo nstrated that all Id2(-/-) fetal thymic progenitors are destined for the T cell lineage, whereas progenitors for T/NK, T, and NK cell lineages were fo und in the control. Interestingly, the total progenitor number was similar between Id2(-/-) and Id2(+/+) embryos analyzed. Expression of Id2 was corre lated with p-NK activity. Our results suggest that Id2 is indispensable in thymic NK cell development, where it most probably restricts bipotent T/NK progenitors to the NK cell lineage.