The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor

Abstract

Diverse innate lymphoid cell (ILC) subtypes have been defined, based on effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways leading to ILC lineage specification remain poorly characterized. Here we demonstrate that transcriptional regulator TOX is required for the in vivo differentiation of common lymphoid progenitors to ILC lineage-restricted cells. In vitro modeling demonstrates that TOX deficiency results in early defects in progenitor cell survival or expansion as well as later stage ILC differentiation. In addition, comparative transcriptome analysis of bone marrow progenitors reveals that TOX-deficient cells fail to upregulate many aspects of the ILC gene program, including Notch gene targets, implicating TOX as a key determinant of early ILC lineage specification.

Diverse developmental pathways of intestinal intraepithelial lymphocytes

“…In the lungs, NKT cells and ILC2s contribute to both the host response against bacterial infections and the initiation of allergic responses 123,124 (not shown).…”

Group 2 innate lymphoid cells protect lung endothelial cells from pyroptosis in sepsis

“…ILC2 in the lungs at baseline and time points up to 36 h after CLP or sham surgery (SS) were detected by flow cytometry and defined as Lin − CD45 + CD90.2 + ST2 + cells (see gating strategy in Supplementary Fig. 1a) 26 . Additional ILC2 markers, including Sca-1, KLRG1, CD25, and CD127 were also used to further confirm ILC2 identification (Supplementary Fig.…”

“…Additional ILC2 markers, including Sca-1, KLRG1, CD25, and CD127 were also used to further confirm ILC2 identification (Supplementary Fig. 1b) 17,26 . The percentage and absolute number of ILC2 in the lungs at 12 h after CLP was significantly increased as compared with that in SS mice, and the ILC2 number remained elevated for at least additional 24 h (Fig.…”

Cellular and molecular regulation of innate inflammatory responses

“…[162][163][164] TOX-deficient mice have diminished numbers of LTi cells, NK cells, ILC1, ILC2 and ILC3 cells, indicating that TOX is required for in vivo differentiation of common lymphoid progenitors into ILC lineage-restricted cells. 165,166 Using novel reporter mice, researchers identified a novel subset of early ILC progenitors (EILPs) with distinctive expression of transcription factor TCF-1. EILPs exclusively and efficiently gives rise to NK cells and all known adult helper ILC lineages and therefore are perhaps the earliest ILC-committed progenitors identified so far.…”