Waves of layered immunity over innate lymphoid cells

Abstract

Innate lymphoid cells (ILCs) harbor tissue-resident properties in border zones, such as the mucosal membranes and the skin. ILCs exert a wide range of biological functions, including inflammatory response, maintenance of tissue homeostasis, and metabolism. Since its discovery, tremendous effort has been made to clarify the nature of ILCs, and scientific progress revealed that progenitor cells of ILC can produce ILC subsets that are functionally reminiscent of T-cell subsets such as Th1, Th2, and Th17. Thus, now it comes to the notion that ILC progenitors are considered an innate version of naïve T cells. Another important discovery was that ILC progenitors in the different tissues undergo different modes of differentiation pathways. Furthermore, during the embryonic phase, progenitor cells in different developmental chronologies give rise to the unique spectra of immune cells and cause a wave to replenish the immune cells in tissues. This observation leads to the concept of layered immunity, which explains the ontology of some cell populations, such as B-1a cells, γδ T cells, and tissue-resident macrophages. Thus, recent reports in ILC biology posed a possibility that the concept of layered immunity might disentangle the complexity of ILC heterogeneity. In this review, we compare ILC ontogeny in the bone marrow with those of embryonic tissues, such as the fetal liver and embryonic thymus, to disentangle ILC heterogeneity in light of layered immunity.

Both Horatio and Polonius: Innate Lymphoid Cells in Tissue Homeostasis and Repair

“…ILC2s from fetal liver or adult bone marrow derive from common lymphoid precursors that, at default, have a genomic organization that favors ILC development and subsequently undergoes rearrangement, tethering, and looping of Id2, GATA-3, and RORα elements to become restricted to an ILC2 progenitor pool ( 18 ). Although genomic alterations driving differentiation to other ILC subsets are less well characterized, ILC1/NK and ILC3 development appear to follow similar organizing principles, as shown in fate mapping experiments tracing the development of liver-resident NK cells from ILC2 progenitors and in distinct ILC3 subsets (NCR + and NCR − ) successively arising in the mouse fetal gut, as recently overviewed ( 19 ).…”

Type 1 immunity enables neonatal thymic ILC1 production

“…On the other hand, cNK cells originate from the bone marrow and develop postnatally to become the primary group-1 ILC population in the spleen and bone marrow within the first 2 weeks of life (19). However, contrary to cNK cells, the ontogeny of the different perinatal ILC1 waves remains elusive (19,21,22). In the thymus, group-1 ILCs are recognized as a rare population, distinct from other peripheral group-1 ILCs (23,24), and can develop from early thymic progenitors (ETPs) both from humans and mice (25)(26)(27)(28).…”

“…Unlike cNK cells, thymic group-1 ILC development depends on IL-7 and the transcription factor GATA3 ( 23 ), similar to ILC1s, ILC2s, and ILC3s ( 30 ). However, whether thymic-derived ILC1s and cNK cells contribute to the peripheral compartments remains unclear ( 22 ). ILC1 numbers increase in all examined tissues during perinatal development in mice from embryonic day 14.5 (E14.5) until postnatal day 3 (P3) ( 19 ).…”

Layered immunity and layered leukemogenicity: Developmentally restricted mechanisms of pediatric leukemia initiation

“…These progenitors include (1) hematopoietic stem cells (HSCs), which have long‐term self‐renewal capacity and can give rise to all blood populations; (2) multipotent progenitors (MPPs), which have only limited self‐renewal capacity yet can give rise to multiple blood populations; and (3) lineage‐restricted myeloid and lymphoid progenitors, which lack long‐term self‐renewal capacity and display varying degrees of differentiation 4–8 . Under normal circumstances, waves of age‐restricted HSCs and MPPs give rise to unique lymphoid and myeloid cell populations that have distinct pathogen‐fighting capabilities, a process often described as “layered immunity.” 9,10 Under abnormal circumstances, the same progenitors may acquire one or more mutations and give rise to age‐biased leukemias, a process we will describe as “layered leukemogenicity.” If we can identify mechanisms that connect layered immunity to layered leukemogenicity, we can potentially identify age‐specific therapeutic vulnerabilities to treat pediatric leukemia patients.…”

“…[4][5][6][7][8] Under normal circumstances, waves of age-restricted HSCs and MPPs give rise to unique lymphoid and myeloid cell populations that have distinct pathogen-fighting capabilities, a process often described as "layered immunity." 9,10 Under abnormal circumstances, the same progenitors may acquire one or more mutations and give rise to age-biased leukemias, a process we will describe as "layered leukemogenicity." If we can identify mechanisms that connect layered immunity to layered leukemogenicity, we can potentially identify age-specific therapeutic vulnerabilities to treat pediatric leukemia patients.…”