An IFN-γ feedback loop
Innate lymphoid cells (ILCs) play important roles in tissue homeostasis and host defense. Type 1 ILCs (ILC1s) produce interferon-γ (IFN-γ) and require the transcriptional master regulator T-bet. The pathways underlying how these cells develop and differentiate have remained poorly understood. Bai et al. found that the adult mouse liver contains a population of Lin–Sca-1+Mac-1+ hematopoietic stem cells (LSM HSCs) that preferentially differentiate into tissue-resident liver ILC1s. They further show that IFN-γ produced by mature ILC1s promotes the expansion and differentiation of LSM HSCs into ILC1s but not natural killer cells. This work expands our understanding of extramedullary hematopoiesis and underscores the unique immune status of the liver.
Science, this issue p. eaba4177
The predominant sites where hematopoiesis occurs change during the course of mammalian development. Bone marrow (BM) hematopoiesis has long been considered the major source of mature blood cells during adulthood, but extramedullary hematopoiesis in other adult organs can occur under certain circumstances and makes a particularly important contribution when the BM is not functional. In particular, the adult liver environment remains compatible with hematopoiesis and contains a few hematopoietic stem cells (HSCs) with long-term capacity for hematopoietic reconstitution.
The pathways leading to the development of tissue-resident lymphocytes, including liver type 1 innate lymphoid cells (ILC1s), remain unclear. The adult mouse liver ILCs include CD49a−CD49b+ conventional natural killer (cNK) cells and CD49a+CD49b− ILC1s. Given the tissue-resident status of CD49a+CD49b− ILC1s in the liver and their impaired reconstitution in mice receiving BM transplants, we investigated whether liver ILC1s could develop from local hematopoietic progenitors during adulthood.
Previous studies have demonstrated that fetal liver HSCs are enriched in a lineage (Lin)-negative population expressing both Mac-1 and Sca-1. We found that the adult mouse liver also contains Lin−Sca-1+Mac-1+ (LSM) HSCs derived from the fetal liver. An analysis of parabiotic mice showed that adult liver LSM cells were strictly tissue resident at steady state. LSM cells purified from adult mouse liver and transferred into sublethally irradiated immmunodeficient mice by portal vein injection were able to generate multiple hematopoietic lineages but preferentially differentiated into ILC1s rather than cNK cells in the recipient liver. Single-cell RNA sequencing analysis showed that LSM cells represented a complex population of various cell subsets and revealed Lin−CD122+CD49a+ cells as a heterogeneous precursor population downstream from LSM cells, with a differentiation potential restricted to liver ILC1s rather than cNK cells. Mechanistically, we could show that deficiency in the gene encoding interferon-γ (Ifng) or one of its receptors (Ifngr1) selectively reduced the frequency and number of ILC1s and not cNK cells in the liver. Delivery of a plasmid containing the interferon-γ (IFN-γ) cDNA to Ifng-deficient mice via hydrodynamic tail-vein injection selectively increased the frequency and number of liver ILC1s but not of liver cNK cells. Moreover, IFN-γ signaling promoted the expansion and differentiation of LSM cells but not of ILC1s, supporting a model in which IFN-γ acts on these local progenitors to promote liver ILC1 development. Previous studies have shown a strict requirement of the transcription factor T-bet for ILC1 development. We showed that T-bet is not required for LSM cell development but is key for the LSM cell differentiation into ILC1s. We then explored the cellular source of IFN-γ that affects liver ILC1 production. ILC1 numbers were unaffected in the absence of T or B cells. By contrast, Ncr1Cre/+Ifngfl/fl mice, in which Ifng expression is conditionally abolished on NKp46+ cells, harbored a selective deficiency of liver ILC1s. We previously demonstrated that conditional deficiency of the transcription factor Eomes in NKp46+ ILCs leads to an absence of cNK cells, with no impact on liver ILC1s, ruling out a role for cNK cells in liver ILC1 development. Because all NKp46+ ILCs producing IFN-γ are either cNK cells or ILC1s, IFN-γ production by ILC1s therefore promotes the development of ILC1s in the liver through its action on their progenitors.
We identified an IFN-γ–dependent loop that amplifies the development of liver ILC1s but not cNK cells locally. Our findings reveal the contribution of extramedullary hematopoiesis to a distinctive regional immune feature within the liver. These results are reminiscent of the local development of macrophages from embryonic precursors that selectively seed the tissues and of the in situ differentiation of lung ILC2s from tissue-resident progenitors. They advance our knowledge of the importance of extramedullary hematopoiesis to cells of lymphoid origin.
In contrast to cNK cells (yellow) derived from the HSCs (blue) in adult BM, tissue-resident liver ILC1s (red) develop locally during adulthood from LSM HSCs (green) derived from the fetal liver. The IFN-γ production by the liver ILC1s themselves promotes their development in situ, through effects on their IFN-γR+ liver progenitors.
The pathways that lead to the development of tissue-resident lymphocytes, including liver type 1 innate lymphoid cells (ILC1s), remain unclear. We show here that the adult mouse liver contains Lin−Sca-1+Mac-1+ hematopoietic stem cells derived from the fetal liver. This population includes Lin−CD122+CD49a+ progenitors that can generate liver ILC1s but not conventional natural killer cells. Interferon-γ (IFN-γ) production by the liver ILC1s themselves promotes the development of these cells in situ, through effects on their IFN-γR+ liver progenitors. Thus, an IFN-γ–dependent loop drives liver ILC1 development in situ, highlighting the contribution of extramedullary hematopoiesis to regional immune composition within the liver.