Single cell analysis defines the divergence between the innate lymphoid cell and lymphoid tissue inducer lineages

The precise lineage relationship between innate lymphoid cells (ILC) and lymphoid tissue inducer (LTi) cells is poorly understood. Using single-cell multiplex transcriptional analysis of 100 lymphoid genes and single-cell cultures of fetal liver precursor cells, we identified the common proximal precursor to these lineages and showed that its bifurcation was marked by the differential induction of the transcription factors PLZF and TCF1. Acquisition of individual ILC subset-specific effector programs was initiated later, at the common ILC precursor stage, by transient expression of mixed ILC1, ILC2 and ILC3 transcriptional patterns whereas, in contrast, LTi cell development did not go through multilineage priming. These findings provide insights into divergent mechanisms of ILC and LTi cell lineage differentiation and establish a high-resolution blueprint of their development.