Deciphering the Innate Lymphoid Cell Transcriptional Program

Abstract

Innate lymphoid cells (ILCs) are enriched at mucosal surfaces, where they provide immune surveillance. All ILC subsets develop from a common progenitor that gives rise to pre-committed progenitors for each of the ILC lineages. Currently, the temporal control of gene expression that guides the emergence of these progenitors is poorly understood. We used global transcriptional mapping to analyze gene expression in different ILC progenitors. We identified PD-1 to be specifically expressed in PLZF ILCp and revealed that the timing and order of expression of the transcription factors NFIL3, ID2, and TCF-1 was critical. Importantly, induction of ILC lineage commitment required only transient expression of NFIL3 prior to ID2 and TCF-1 expression. These findings highlight the importance of the temporal program that permits commitment of progenitors to the ILC lineage, and they expand our understanding of the core transcriptional program by identifying potential regulators of ILC development.

Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network

“…Up-regulation of Zbtb16, Nfil3, Id2, and Il2rb in Bcl11b-deficient cells provides both growth support and identity functions for NK and ILC fates outside of the conventional αβ T-cell pathway (43,53,57,58). Many Bcl11b KO cells also up-regulate the phase 1-specific Notch-negative feedback regulator, Nrarp, which is also highly expressed in NK cells.…”

“…Indeed, the Kyoto Encyclopedia of Genes and Genomes pathway most highly enriched in our Bcl11b-repressed gold-standard gene set was NK cell-mediated cytotoxicity (SI Appendix, Fig. S6A), and multiple genes were shared with gene sets that distinguish ILC from T cells (42,43). However, the gold-standard set as a whole was distinct from top Bcl11b-regulated genes in DP cells.…”

Downregulation of E Protein Activity Augments an ILC2 Differentiation Program in the Thymus

“…Id2-deficient mice lack not only NK cells but also all ILC subsets (21). Id2 is highly expressed in both ILCs and ILC progenitors (6,22,23). In the thymus, E2A and HEB are both expressed and play redundant roles in controlling T cell differentiation (24–30).…”

Type two innate lymphoid cells: the Janus cells in health and disease

“…Since ILC2s have been identified as IL‐33 or IL‐25 responsive innate lymphoid cells, all murine innate lymphoid cells, lineage‐negative CD45 + cells, that express the IL‐33 receptor, ST2 or IL‐25 (IL‐17RB) receptor would be considered as ILC2s . However, several other cell surface markers have been described for further distinction of both murine and human ILC2s among all innate lymphoid cell population, including Inducible T cell Costimulator (ICOS), Killer cell lectin‐like receptor subfamily G member 1 (KLRG‐1) and cytokine receptors IL‐7 receptor‐α, and IL‐2 receptor‐α . Murine but not human ILC2s also express CD90 (Thy1) .…”