Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation

Abstract

Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. Here, we identify circulating and tissue ILCPs in humans that fail to express the transcription factors and cytokine outputs of mature ILCs but have these signature loci in an epigenetically poised configuration. Human ILCPs robustly generate all ILC subsets in vitro and in vivo. While human ILCPs express low levels of retinoic acid receptor (RAR)-related orphan receptor C (RORC) transcripts, these cells are found in RORC-deficient patients and retain potential for EOMES natural killer (NK) cells, interferon gamma-positive (IFN-γ) ILC1s, interleukin (IL)-13 ILC2s, and for IL-22, but not for IL-17A ILC3s. Our results support a model of tissue ILC differentiation ("ILC-poiesis"), whereby diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.

A Major Population of Functional KLRG1– ILC2s in Female Lungs Contributes to a Sex Bias in ILC2 Numbers

“…Murine parabiosis experiments showed that in adults ~95% of ILC2s do not apparently circulate in blood or replenish from blood-borne precursors, although small numbers of ILC precursors were noted in blood (43). Similarly, rare ILC precursors and ILC2s were identified in human blood (62). Most tissue ILC2s are thought to arise from precursors seeded into tissues before birth, and there is a rapid rise of mature ILC2s in lungs and small intestine in the first weeks after birth (39, 44, 45).…”

Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells

“…33 However, we demonstrate that human NKp44 1 bona fide ILC3s from secondary lymphoid tissues can develop into functional equivalents of NK cells, and this developmental pathway, which demonstrates many similarities to NK-cell differentiation from stage 3 precursors, 17,18 might provide cytotoxic protection at mucosal barriers.…”

Les cellules lymphoïdes innées

“…Toutefois, il semblerait que chez l'adulte, des précurseurs périphériques existent. En effet, des précurseurs de cellules NK ont été trouvés en dehors de la moelle osseuse chez l'homme comme chez la souris [30] et des précurseurs des ILC3 ont été identifiés dans les amygdales et le sang périphérique [57] chez l'homme [31]. Le rôle des CHILP de la moelle osseuse chez l'adulte reste à définir.…”