Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells

AUTHORS

Jacobse JJustin , Brown RERachel E , Li JJing , Pilat JMJennifer M , Pham LLy , Short SPSarah P , Peek CTChristopher T , Rolong AAndrea , Washington MKM Kay , Martinez-Barricarte RRuben , Byndloss MXMariana X , Shelton CCatherine , Markle JGJanet G , Latour YLYvonne L , Allaman MMMargaret M , Cassat JEJames E , Wilson KTKeith T , Choksi YAYash A , Williams CSChristopher S , Lau KSKen S , Flynn CRCharles R , Casanova JLJean-Laurent , Rings EHHMEdmond H H M , Samsom JNJanneke N , Goettel JAJeremy A . Cell reports. 2023 02 17; 42(2). 112128

PMID: 36807140[PubMed].

ABSTRACT

The cytokine interleukin-23 (IL-23) is involved in the pathogenesis of inflammatory and autoimmune conditions including inflammatory bowel disease (IBD). IL23R is enriched in intestinal Tregs, yet whether IL-23 modulates intestinal Tregs remains unknown. Here, investigating IL-23R signaling in Tregs specifically, we show that colonic Tregs highly express Il23r compared with Tregs from other compartments and their frequency is reduced upon IL-23 administration and impairs Treg suppressive function. Similarly, colonic Treg frequency is increased in mice lacking Il23r specifically in Tregs and exhibits a competitive advantage over IL-23R-sufficient Tregs during inflammation. Finally, IL-23 antagonizes liver X receptor pathway, cellular cholesterol transporter Abca1, and increases Treg apoptosis. Our results show that IL-23R signaling regulates intestinal Tregs by increasing cell turnover, antagonizing suppression, and decreasing cholesterol efflux. These results suggest that IL-23 negatively regulates Tregs in the intestine with potential implications for promoting chronic inflammation in patients with IBD.