Abstract
Innate lymphoid cells (ILCs) play a central role conferring protection at the mucosal frontier. In this study, we have identified a requirement of the transcription factor Zbtb1 for the development of RORγt+ ILCs (ILC3s). Zbtb1-deficient mice lacked NKp46+ ILC3 cells in the lamina propria of the small and large intestine. This requirement of Zbtb1 was cell intrinsic, as NKp46+ ILC3s were not generated from Zbtb1-deficient progenitors in bone marrow chimeras and Zbtb1-deficient RORγt+ CCR6−NKp46− ILC3s didn't generate NKp46+ ILC3s in co-cultures with OP9-DL1 stroma. In correlation with this impairment, Zbtb1-deficient ILC3 cells failed to upregulate T-bet expression, and to acquire IFN-γ production characteristic of NKp46+ cells. Finally, absence of NKp46+ILC3 cells combined with the absence of T-cells in Zbtb1-deficient mice, led to a transient susceptibility to C. rodentium infections. Altogether, these results establish that Zbtb1 is essential for the development of NKp46+ ILC3 cells.
Highlights
The intestinal mucosa is a permeable barrier that allows absorption of nutrients while preventing invasion of pathogenic bacteria
To investigate if Zbtb1 was required for the function of ILC3 cells in protecting mice from bacterial infections, we evaluated if ScanT mice were more susceptible to C. rodentium infections
We have uncovered an essential requirement of the transcription factor Zbtb1 for the generation of NKp46+ILC3 cells
Summary
The intestinal mucosa is a permeable barrier that allows absorption of nutrients while preventing invasion of pathogenic bacteria. ILCs represent a family of innate effectors that lack expression of lineage-specific markers corresponding to T, B and myeloid cells. They develop from a common lymphoid progenitor (CLP, Lin-Sca-1lowckitlowCD127+) and express CD127 (IL-7Rα) as lymphoid cells, they lack rearranged antigen receptors such as the BCR in B-cells and TCR in T-cells [2, 3]. Rorγt+ ILC3 cells are a heterogeneous population that is abundant at mucosa sites. They can be divided into three main subsets based on their role during embryogenesis and their cell-surface expression of the natural cytotoxicity receptor NKp46 [6]. IL-22-deficient mice [13] and genetic disruption of ILC3 development, as it occurs in mice deficient for T-bet (Tbx21-deficient), TCF-1-deficient or AhR-deficient mice are highly susceptible to C. rodentium infections [14,15,16]
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