Differential Expression of the Transcription Factor GATA3 Specifies Lineage and Functions of Innate Lymphoid Cells

Lymphoid tissue inducer (LTi) cells are regarded as a subset of innate lymphoid cells (ILCs). However, these cells are not derived from the ILC common progenitor, which generates other ILC subsets and is defined by the expression of the transcription factor PLZF. Here, we examined transcription factor(s) determining the fate of LTi progenitors versus non-LTi ILC progenitors. Conditional deletion of Gata3 resulted in the loss of PLZF+ non-LTi progenitors but not the LTi progenitors that expressed the transcription factor RORγt. Consistently, PLZF+ non-LTi progenitors expressed high amounts of GATA3, whereas GATA3 expression was low in RORγt+ LTi progenitors. The generation of both progenitors required the transcriptional regulator Id2, which defines the common helper-like innate lymphoid progenitor (ChILP), but not cytokine signaling. Nevertheless, low GATA3 expression was necessary for the generation of functionally mature LTi cells. Thus, differential expression of GATA3 determines the fates and functions of distinct ILC progenitors. [Display omitted] •High GATA3 expression is required for the development of non-LTi ILC progenitors•GATA3 is dispensable for the development of RORγt-expressing LTi progenitors•Low GATA3 expression is essential for the acquisition of LTi cell function•GATA3 and Id2 determine ILC lineage fates before cytokine-mediated ILC maturation Lymphoid tissue inducer (LTi) cells are regarded as a subset of innate lymphoid cells (ILCs). Zhong et al. show that the generation of both non-LTi and LTi progenitors requires the transcriptional regulator Id2, but is distinguished by the differential requirement for the transcription factor GATA3. Their findings suggest that non-LTi ILCs are the bona fide innate counterparts of CD4+ T effector cells.