Control of Intestinal Type 3 Immunity by the Unfolded Protein Response Sensor IRE1 in Antigen Presenting Cells

The unfolded protein response (UPR) is an essential cellular program maintaining intestinal homeostasis by acting on several cell types. However, whether the UPR sensor IRE1 acts on dendritic cells (DCs) and other antigen presenting cells (APCs) for shaping intestinal immunity remains poorly defined.

Here, we dissect the role of the RNase domain of the UPR sensor IRE1 in intestinal CD11c⁺ APCs, using IRE1 RNase reporter mice and conditional loss-of-function models for IRE1 and its downstream transcription factor XBP1s.

We identify robust IRE1 RNase activity in intestinal conventional DC subsets, DCs associated to crypto patches and isolated lymphoid follicles (CIA-DCs) and macrophages, independently of microbial signals. Targeted ablation of IRE1 RNase in the intestinal CD11c⁺ compartment provoked spontaneous features of type 3 immunity in the small intestine, characterized by increased antimicrobial peptides and neutrophil recruitment, as well as elevated production of IL-17 and IL-22 by Th17 cells and group 3 innate lymphoid cells (ILC3s). This dysregulated activation required IRE1 RNase but occurred independently of XBP1s, implicating Regulated IRE1 Dependent Decay (RIDD) rather than canonical XBP1s signaling. Mechanistically, distinct IRE1 RNase-deficient intestinal APC subtypes such as cDCs exhibited increased Il6, Il1b and Ccl22 transcript levels, whereas cDCs and CIA-DCs showed marked reductions in IL-22BP expression, a profile known to increase IL-22 bioavailability and enhance Th17/ILC3 responses.

Collectively, our findings uncover IRE1 RNase in intestinal CD11c⁺ APC subtypes as a critical checkpoint restraining type 3 immunity and maintaining intestinal immunity in steady state, highlighting its potential as therapeutic target for intestinal inflammation.