Transcription factor BHLHE40 expression in group 3 innate lymphoid cells and RORγt⁺ antigen-presenting cells coordinates intestinal immunity.

A key feature of the intestinal immune system is balancing pathogen defense with antigen-specific tolerance to commensal bacteria. Here, using conditional deletion models, we identified the transcription factor BHLHE40 as a central regulator of group 3 innate lymphoid cell (ILC3)- and RORγt⁺ antigen-presenting cell (APC)-dependent mucosal immunity. In ILC3s, BHLHE40 drove transcription of cytokine effector programs and maintenance of mucosal immunity. Cytokine TL1A stimulation and inflammation induced Bhlhe40 expression, amplifying these programs through epigenetic modulation of chromatin accessibility at effector loci. Bhlhe40 was also highly expressed in RORγt⁺ APCs, where it was required for the generation of antigen-specific Tregs. In parallel, BHLHE40 integrated microbial cues to promote expression of the co-stimulatory molecule OX40L by ILC3s, further promoting antigen-specific Treg induction. Together, these findings define Bhlhe40 as a coordinated regulator of barrier immunity and support a model in which ILC3s and RORγt⁺ APCs act in concert to shape antigen-specific intestinal immunity.