Ly49E separates liver ILC1s into embryo-derived and postnatal subsets with different functions

Abstract

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.

Embryonic and neonatal waves generate distinct populations of hepatic ILC1s

“…A previous study ( 56 ) showed that Ly49E − ILC1s up-regulate Ly49E in the liver after transfer into cNK/ILC1-deficient mice. Thus, Ly49E might be a marker not only for embryonic ILC1s ( 57 ) but also for a specific niche. After birth, embryonic ILC1s reduce their proliferative activity, consistent with an ongoing effector differentiation toward late, cytotoxic ILC1s, potentially allowing the second wave of neonatal helper-like ILC1s to colonize the liver.…”

NK Cells and Other Cytotoxic Innate Lymphocytes in Colorectal Cancer Progression and Metastasis

“…Recently, our group [ 29 ] and others [ 34 , 44 ] have found murine Eomes −/lo ILC1 able to express perforin and granzyme A, B, and C and to kill target cells. Liver granzyme A + ILC1 are sensitive to Hobit deletion [ 30 , 44 ] and can originate from fetal ILC1 [ 107 ] or as a product of ILC3–ILC1 plasticity [ 29 ], but not from NK cells. In humans, a population of cytotoxic ILC1 was also found in the gut in conditions of IBD; this population is characterized by the expression of CD127, CD94, granulysin, and perforin and the presence of features of both CD127 + ILC1 and CD94 + NK cells [ 31 ].…”

The unique role of innate lymphoid cells in cancer and the hepatic microenvironment

“…A recent study showed that hepatic ILC1s derived from different origins differ in their function [ 65 ]. By using inducible reporter mice to fate-map hematopoietic stem cells, but not lineage-restricted progenitors, the authors showed that a population of Ly49E + ILC1s was primarily fetus-derived and decreased with age, while Ly49E − ILC1s retained the ability to be replenished from adult progenitors.…”

“…By using inducible reporter mice to fate-map hematopoietic stem cells, but not lineage-restricted progenitors, the authors showed that a population of Ly49E + ILC1s was primarily fetus-derived and decreased with age, while Ly49E − ILC1s retained the ability to be replenished from adult progenitors. Functionally, Ly49E + ILC1s expressed higher levels of granzymes and lysed target cells more efficiently in vitro, suggesting a distinct role for these fetus-derived cells in the host defense of neonates, whose adaptive immune system is not fully developed [ 65 ].…”