T Cell Factor 1 Is Required for Group 2 Innate Lymphoid Cell Generation

Abstract

SUMMARY Group 2 innate lymphoid cells (ILC2) are innate lymphocytes that confer protective type 2 immunity during helminth infection and are also involved in allergic airway inflammation. Here we report that ILC2 development required T cell factor 1 (TCF-1, the product of the Tcf7 gene), a transcription factor also implicated in T cell lineage specification. Tcf7−/− mice lack ILC2, and were unable to mount ILC2-mediated innate type 2 immune responses. Forced expression of TCF-1 in bone marrow progenitors partially bypassed the requirement for Notch signaling in the generation of ILC2 in vivo. TCF-1 acted through both GATA-3-dependent and GATA-3-independent pathways to promote the generation of ILC2. These results are reminiscent of the critical roles of TCF-1 in early T cell development. Hence, transcription factors that underlie early steps of T cell development are also implicated in the development of innate lymphoid cells.

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

“…RBP-Jk deletion selectively decreased IL-22-producing NKp46 + IL-7Ra + ILCs in the lamina propria but not in the Peyer's patches (45). Epigenetic analysis revealed that IL-7Ra expression in ILC2 cells was directly regulated by TCF1, which was shown to be a direct target of the Notch-RBP-Jk pathway in T cells (46,47). In fact, we also found ICN1 binding on the promoter region (231 kb upstream from the TSS) of TCF1 in gd T cells (Fig.…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…1). Progressive commitment to the ILC lineage is also dependent, to varying degrees, on a multitude of transcription factors including GATA‐3, TOX, TCF‐1 and NFIL316, 17, 18, 19, 20, 21 (and reviewed in detail in references 10 and 22). …”

Innate Lymphoid Cells in Type 2 Immune Responses

“…Interestingly, data indicate that the role of TCF-1 in ILC development is not limited to ILC2 as numbers of RORct ? ILC3 are also reduced in the absence of this TF (Mielke et al 2013;Yang et al 2013).…”

“…TCF-1 directly drove Il7r expression, allowing ILC2 responsiveness to this cytokine. Forced TCF-1 expression in bone marrow cells in vitro, however, appears to by-pass the need for Notch signaling as the cells up-regulate many of the factors associated with ILC2 function independently of Notch signaling (Yang et al 2013). Interestingly, data indicate that the role of TCF-1 in ILC development is not limited to ILC2 as numbers of RORct ?…”

“…Indeed, using a pan-Notch inhibitor, Yang et al (2013) demonstrated that Notch signaling was important in ILC2 development in vivo. Downstream from Notch, signaling through the T cell factor (TCF)-1 TF was vital for ILC2 maturation, since Tcf7 (which encodes TCF-1) knockout mice lacked mature ILC2 and their associated immune responses (Yang et al 2013). TCF-1 directly drove Il7r expression, allowing ILC2 responsiveness to this cytokine.…”