AbstractFor many years, human peripheral blood natural killer (NK) cells have been divided into functionally distinct CD3−CD56brightCD16−and CD3−CD56dimCD16+subsets. Recently, several groups of innate lymphoid cells (ILC), distinct from NK cells in development and function, have been defined in mouse. A signature of genes present in mouse ILC except NK cells, defined by Immunological Genome Project studies, is significantly over-represented in human CD56brightcells, by gene set enrichment analysis. Conversely, the signature genes of mouse NK cells are enriched in human CD56dimcells. Correlations are based upon large differences in expression of a few key genes. CD56brightcells show preferential expression of ILC-associatedIL7R(CD127),TNFSF10(TRAIL),KIT(CD117),IL2RA(CD25), CD27,CXCR3, DPP4(CD26),GPR183, and MHC class II transcripts and proteins. This could indicate an ontological relationship between human CD56brightcells and mouse CD127+ILC, or conserved networks of transcriptional regulation. In line with the latter hypothesis, among transcription factors known to impact ILC or NK cell development,GATA3,TCF7(TCF-1),AHR,SOX4, RUNX2, andZEB1transcript levels are higher in CD56brightcells, whileIKZF3(AIOLOS),TBX21(T-bet),NFIL3(E4BP4),ZEB2,PRDM1(BLIMP1), andRORAmRNA levels are higher in CD56dimcells.