Type 1 innate lymphoid cells (ILC1s) represent the predominant population of liver ILCs and function as important effectors and regulators of immune responses, but the cellular heterogeneity of ILC1s is not fully understood. Here, single-cell RNA sequencing and flow cytometric analysis demonstrated that liver ILC1s could be dissected into Ly49E+ and Ly49E populations with unique transcriptional and phenotypic features. Genetic fate-mapping analysis revealed that liver Ly49E+ ILC1s with strong cytotoxicity originated from embryonic non–bone marrow hematopoietic progenitor cells (HPCs), persisted locally during postnatal life, and mediated protective immunity against cytomegalovirus infection in newborn mice. However, Ly49E ILC1s developed from BM and extramedullary HPCs after birth, gradually replaced Ly49E+ ILC1s in the livers with age, and contained the memory subset in recall response to hapten challenge. Thus, our study shows that Ly49E dissects liver ILC1s into two unique subpopulations, with distinct origins and a bias toward neonatal innate or adult immune memory responses.

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