GFI1B specifies developmental potential of innate lymphoid cell progenitors in the lungs.

Tissue-resident innate lymphoid cells (ILCs) play a vital role in the frontline defense of various tissues, including the lung. The development of type 2 ILCs (ILC2s) depends on transcription factors such as GATA3, RORα, GFI1, and Bcl11b; however, the factors regulating lung-resident ILC2s remain unclear. Through fate mapping analysis of the paralog transcription factors GFI1 and GFI1B, we show that GFI1 is consistently expressed during the transition from progenitor to mature ILC2s. In contrast, GFI1B expression is limited to specific subsets of bone marrow progenitors and lung-resident ILC progenitors. We found that GFI1B⁺ lung ILC progenitors represent a multi-lineage subset with tissue-resident characteristics and the potential to form lung-derived ILC subsets and liver-resident ILC1s. Loss of GFI1B in bone marrow progenitors led to the selective loss of lung-resident IL-18R⁺ ILCs and mature ILC2, subsequently preventing the emergence of effector ILCs that could protect the lung against inflammatory or tumor challenge. Editor's summary: Most innate lymphoid cells (ILCs) develop from lineage-restricted ILC progenitors in the bone marrow, but certain tissues such as the lungs are believed to harbor local ILC progenitor populations. How these local ILC progenitor pools are maintained remains unclear. Using dual reporter mice, Huang et al. mapped expression of the paralog transcription factors GFI1 and GFI1B in ILCs and their progenitors. GFI1B expression alone identified bone marrow and lung ILC progenitors that retained potential to differentiate into multiple ILC lineages. Loss of GFI1B-dependent ILCs impaired type 2 ILC development in the lungs, leading to reduced papain-induced inflammation but impaired protection against establishment of lung tumors. Together, these findings identify GFI1B expression as hallmark of lung-resident ILCs that retain multilineage developmental potential. —Claire Olingy [ABSTRACT FROM AUTHOR]