 In a recent study, researchers have identified RUNX3 as a protein that drives cell differentiation into specific types of innate lymphoid cells, OILCs, that reside in the gut. These cells play important roles during normal immune responses to infection and in inflammatory conditions such as colitis, making it critical to understand more about how they develop. Protein lymphoid progenitors, or CLPs, give rise to numerous types of immune cells, including B cells, T cells, and three major subtypes of ILCs, ILC1, II, and III, through a sequence of differentiation events. This so-called lineage specification is driven largely by proteins called transcription factors, which turn on whole suites of genes to specify the characteristics and behaviors of a given cell type. Transcription factors in the RUNX family are known to have roles in lineage specification in T cell subsets, which share some features with ILCs. For this reason, researchers were interested in the role of RUNX3 in ILC differentiation in mice. They found that RUNX3 is expressed in both ILC1 and ILC3 cells, but not ILC2 cells. Furthermore, eliminating the expression of RUNX3 and its cofactor, CBF-beta in ILCs and their precursors, led to lower numbers of ILC3 cells and ILC1 cells. At the same time, there was an accumulation of a previously undescribed precursor cell type referred to as ILCLNs for CD127-positive ILC lineage negative cells, suggesting that the cells stalled in their development at this stage. However, the lineage specification to that point remained normal. The researchers also observed that RUNX3 regulates two genes that are important for ILC3 identity, further supporting a role for RUNX3 in the final step of ILC3 specification. Importantly, mice lacking RUNX3 expression in ILC1 and a subset of ILC3 cells were more susceptible to infection with the bacterium cirrodentium. The mice without RUNX3 had higher counts of cirrodentium in the spleen and shorter colons, indicating more severe infection. The mice also expressed lower levels of the cytokines that activate the appropriate immune response to pathogen attack, and they exhibited more persistent inflammation-related damage after infection. Together, these findings reveal the critical role of RUNX3 in the differentiation of cells that protect the gut from infection and inflammation, and suggest RUNX3 as an important target for future research relevant to colitis and other intestinal inflammatory disorders.