Tissue-Resident Group 2 Innate Lymphoid Cells Differentiate by Layered Ontogeny and In Situ Perinatal Priming

Abstract

The perinatal period is a critical window for distribution of innate tissue-resident immune cells within developing organs. Despite epidemiologic evidence implicating the early-life environment in the risk for allergy, temporally controlled lineage tracing of group 2 innate lymphoid cells (ILC2s) during this period remains unstudied. Using complementary fate-mapping approaches and reporters for ILC2 activation, we show that ILC2s appeared in multiple organs during late gestation like tissue macrophages, but, unlike the latter, a majority of peripheral ILC2 pools were generated de novo during the postnatal window. This period was accompanied by systemic ILC2 priming and acquisition of tissue-specific transcriptomes. Although perinatal ILC2s were variably replaced across tissues with age, the dramatic increases in tissue ILC2s following helminth infection were mediated through local expansion independent of de novo generation by bone marrow hematopoiesis. We provide comprehensive temporally controlled fate mapping of an innate lymphocyte subset with notable nuances as compared to tissue macrophage ontogeny.

The interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life

“…33 A recent publication showed that perinatal signals leading to expansion of neonatal ILC2s are important to maintain even the adult pool of ILC2s. 38 This perinatal expansion of ILC2s was independent of commensal microbiota as it occurred also in GF mice. As interactions between an individual SPF consortium and a defined diet are very complex, it is not unlikely that a combination of dietary and microbial signals contributes to this event.…”

“…A recent publication showed that perinatal signals leading to expansion of neonatal ILC2s are important to maintain even the adult pool of ILC2s . This perinatal expansion of ILC2s was independent of commensal microbiota as it occurred also in GF mice.…”

‘Layered immunity’ and the ‘neonatal window of opportunity’ – timed succession of non‐redundant phases to establish mucosal host–microbial homeostasis after birth

“…Consistent with a more innate immune function, neonatal T cells were shown to produce tumor necrosis factor (TNF) and CXCL8 . Age‐dependent qualitative differences have also been identified within the ILC compartment . EOMES + natural killer cells with a robust effector phenotype populate the human neonatal intestine and might provide protection until T‐cell effector cells have matured …”

“…91,97 Age-dependent qualitative differences have also been identified within the ILC compartment. 98 EOMES + natural killer cells with a robust effector phenotype populate the human neonatal intestine and might provide protection until T-cell effector cells have matured. 99 Clearly, developmental mechanisms contribute significantly to the initial adaptation to microbial exposure.…”

E proteins orchestrate dynamic transcriptional cascades to suppress ILC2 differentiation

“…which play important roles in initiating type 2 immunity (1). They are enriched in barrier locations such as the lung, intestine and skin (2). They respond to signals released by tissue damages, namely IL-25, IL-33 and TSLP, and produce type 2 cytokines primarily consisting of IL-5, IL-9 and IL-13 (3).…”