The common dependency of NK cells, Rorγt- and RORα-dependent ILCs on Id2 for their development suggests that these cell populations are derived from a common Id2-dependent precursor (Fig. 1), although it cannot

presently be excluded that Id2 is not required for the development of ILCs and NK cells at the level of a common precursor but at later stages of development. It is therefore important to determine whether all ILCs and NK cells are derived from one common NK/ILC precursor or develop independently from an upstream, uncommitted, precursor such as the common lymphoid precursor. Validation of this idea requires Alisertib supplier identification of this precursor cell. Using Id2-GFP reporter mice, Beltz and colleagues identified an Id2high CD117intermediateCD127high Flt3− population in the bone marrow [[19]]. These cells lack any NK markers but differentiate in vitro to NK cells when cultured with IL-7

plus IL-15. It might be possible that those cells also have the capacity to differentiate into Rorγt+ ILCs under the influence of other cytokines. Regardless of whether Id2 controls mTOR inhibitor differentiation of a common NK-cell and ILC precursor or not, the continued expression of Id2 and the consequent downregulation of the activity of the E proteins may be required for the maintenance of the ILC/NK-cell lineages [[20]], mirroring the requirement of continued expression of E2A proteins for B-cell development [[21]]. TOX is an HMG box transcription factor that is expressed in several stages of T-cell development in the thymus. Genetic ablation of Tox results in strong inhibition of the transition from CD4+CD8+ Methocarbamol double positive

thymocytes to CD4+ single positive T cells, and, as a consequence, there are no CD4+ T cells in Tox−/− mice [[22]]. TOX is also expressed in LTi and NK cells, numbers of which are significantly reduced in Tox-deficient mice [[22, 23]]. As a consequence, almost no lymph nodes are present in these animals, with the exception of small numbers of phenotypically abnormal Peyer’s patches. These data suggest that TOX is expressed in a precursor of both LTi and NK cells. The observation that enforced expression of Id2 in Tox−/− precursor cells is insufficient to overcome the Tox deficiency [[23]] may suggest that TOX does not function upstream of Id2; however it cannot be excluded that TOX does act upstream of Id2 but that it also controls other essential targets and that this latter function cannot be overcome by introducing Id2 in Tox-deficient cells.