Role for B-cell lymphoma 6 in intestinal innate lymphoid cell homeostasis and inflammatory disease

Abstract

Abstract Group 3 innate lymphoid cells (ILC3) are critical for intestinal homeostasis. The functional activity of ILC3 must be tightly regulated as cytokines (e.g. IL-17 and IL-22) produced by these cells are critical for antimicrobial immune defense but can also contribute to intestinal disease when produced in excess. This regulation is achieved via incompletely defined transcriptional networks that include B-cell lymphoma 6 (BCL6), which we recently demonstrated is critical for maintaining ILC1- and ILC3-specific gene expression programs during homeostasis (Pokrovskii et al 2019). We now show that Bcl6-deficient small intestine lamina propria ILC3 exhibit elevated expression of the transcription factors retinoic acid receptor-related orphan nuclear receptor alpha (RORα) and RORγt. These factors are known to support ILC3 cytokine expression, potentially explaining elevated Il17a and Il17f expression by Bcl6-deficient ILC3. Of note, expression of Il22ra2 (IL-22 binding) was also markedly increased in these ILC3, likely limiting bioavailability of IL-22. Accordingly, these mice exhibit marked reduction in IL-22-dependent expression of epithelium-associated anti-microbial peptides in the terminal ileum. Of note, Bcl6ΔILC mice exhibited augmented susceptibility to dextran sodium sulfate-induced inflammatory bowel disease. Thus, BCL6 expression in ILC3-intrinsic BCL6 expression is important for mucosal immune defense and limiting intestinal inflammation.