Divergent roles for STAT4 in shaping effector differentiation of ILC1 and NK cells during gut inflammation

Abstract Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require the transcription factor STAT4 to elicit rapid effector responses during infections. Herein, by combining genetic and transcriptomic approaches, we revealed that STAT4 played an unexpected divergent role in regulating effector differentiation of murine ILC1 and NK cells during intestinal inflammation. Stat4 deletion in Ncr1-expressing cells led to an increased generation of cytotoxic ILC1 in the inflamed large intestine. By contrast, Stat4-deficient NK cells showed impaired terminal differentiation, characterized by lower levels of IRF-8 and KLRG1. STAT4 expression in NCR+ innate lymphocytes restrained gut inflammation and type 2 adaptive T cells in the large intestine. Collectively our data shed light on distinctive mechanisms of transcriptional regulation driven by STAT4 in NK cells and ILC1 required for protection during intestinal inflammation. Italian Association for Cancer Research (AIRC) [MFAG-21311], by Institut Pasteur (France), Transversal Research Program program.