| The Id2 transcriptional repressor is essential for the development of natural killer (NK) cells, Lymphoid Tissue inducing (LTi) cells and secondary lymphoid tissues. Id2 was proposed to regulate NK and LTi-lineage specification from multipotent progenitors through suppression of E proteins. To assess this hypothesis, we analyzed Id2+/+ and Id2-/- mice to identify the developmental stage at which Id2 becomes necessary for NK cell differentiation in the bone marrow (BM). NK cell progenitors are present in normal numbers in the BM of adult Id2-/- mice, demonstrating that Id2 is not essential for NK lineage specification. However, NK progenitors are reduced in the thymus of developing 1d2-/- embryos, suggesting that a differential requirement exists for Id2 in NK-lineage specification in the fetal thymus and adult BM. Importantly, though Id2 is not required for the specification of NK lineage cells in the adult BM, it is essential for the development of mature (m)NK cells. Id2 regulates NK and LTi cell development via the inhibition of E proteins, since a reduction in E protein activity, through deletion of E24, overcomes the need for Id2 in the development of BM mNK cells, LTi cells and secondary lymphoid tissues. However, mNK cells are not restored in the blood or spleen of Id2-/-E2A-/- mice suggesting a role for Id2 in suppression of alternative E proteins after maturation. Interestingly, the few splenic mNK cells in Id2-/- and Id2-/-E2A-/- mice have characteristics of thymus-derived NK cells, which develop in the absence of Id2 in adult mice. However, though these cells are thymus-dependent, they also express intracellular CD3 epsilon, consistent with an alternative classification of these cells as "NK-like" T lymphocytes. These discoveries highlight the importance of accurately and reliably distinguishing between NK and T lymphocytes, particularly when evaluating small populations of NK cells. Notably, we also find that the related family member Id3 influences efficient NK cell development. Taken together, our findings redefine the essential functions of Id proteins in lymphoid development and provide insight into the dynamic regulation of E and Id proteins in this process. |
