Zbtb1 controls NKp46⁺ ROR-gamma-T⁺ innate lymphoid cell (ILC3) development

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.