TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow

Abstract

The cellular and molecular events that drive early innate lympoid cell (ILC) development remain poorly understood. We show that transcription factor TCF-1 is required for the efficient generation of all known adult ILC subsets and their precursors. Using novel reporter mice, we identified a new subset of early ILC progenitors (EILP) that expressed high amounts of TCF-1. EILP lacked efficient T and B lymphocyte potential, but efficiently gave rise to NK cells and all known adult helper-ILC lineages, indicating that they are the earliest identified ILC-committed progenitors. Our results suggest that upregulation of TCF-1 expression denotes the earliest stage of ILC fate specification. The discovery of EILP provides a basis to decipher additional signals that specify the ILC fate.

Cellular and molecular regulation of innate inflammatory responses

“…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. 167,168 The interaction of the TOX, TCF-1 and other transcription factors and epigenetic factors in the development of ILCs cells awaits further investigation.…”

Tissue-resident natural killer cells in the livers

“…For example, TCF1 and NFIL3 are responsible for the generation of ILC progenitors, therefore affecting the development of trNK cells, cNK cells as well as other mature ILC subsets (Geiger et al, 2014;Seillet et al, 2014b;Yang et al, 2015;Yu et al, 2014). Notably, in NFIL3-deficient mice, CD49a 2016).…”

A doppelgänger of T cell development

“…6 On the other hand, the earliest described ILC progenitors do not have detectable T-cell potential. 4 This suggests that mechanisms of repression of the T-cell lineage are part of the early ILC transcriptional program. Factors controlling the generation of EILP and commitment to the ILC lineage have not yet been established.…”

“…5 In ILCs, TCF-1 is known to be required for the development of both helper and killer ILC progenitors. 4 However, the developmental stage at which it is required and its function remain unknown. A tempting speculation is that TCF-1 is required at or after the EILP stage, to drive the expression of helper factors in developing helper ILCs, and works together with RUNX to silence helper genes in developing natural killer cells (NK), mirroring its function in thymocyte development.…”

“…Factors controlling the generation of EILP and commitment to the ILC lineage have not yet been established. Candidates such as NFIL3, TOX, or Id2 might fulfill these functions since they are expressed highly in EILP, 4 and are required for ILC but not early T-cell development. Such factors could play unique functions in ILC development, and control the divergence of innate versus adaptive lineages.…”