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From the Journals

Link Between Key Immune Pathways in IBD

IL-23 may activate CTLA-4 on ILC3s, which is crucial for gut homeostasis and may have implications for treating IBD and cancer.

Conexiant

A study published in Nature has identified a previously unknown connection between two major immune pathways that regulate health, immunity, and inflammation in the intestine.

Researchers at Weill Cornell Medicine in New York City discovered that interleukin-23 (IL-23), a cytokine implicated in various autoimmune diseases, activates the immunoregulatory molecule CTLA-4 on group 3 innate lymphoid cells (ILC3s) in the gut, making the IL-23–ILC3–CTLA-4 axis critical for maintaining gut homeostasis by balancing the pro-inflammatory effects of IL-23. This pathway appears to be impaired in patients with inflammatory bowel disease (IBD).

Single-cell RNA sequencing was used to study the effects of IL-23 on different immune cell types in the healthy intestine, revealing that IL-23 potently activates CTLA-4 in ILC3s. Blocking the CTLA-4 pathway in these cells led to severe intestinal inflammation in mice.

The team also confirmed the relevance of their findings in human IBD patients using samples from the Jill Roberts Institute Live Cell Bank. They analyzed intestinal biopsies from 20 patients with Crohn's disease and 20 age- and gender-matched healthy controls. The researchers found:

  • A significantly increased frequency of CTLA-4+ ILC3s in Crohn's disease patients compared to healthy controls
  • A significant positive correlation between the frequencies of CTLA-4+ ILC3s and free PD-L1+ intestinal myeloid cells within the same biopsies of IBD patients
  • The abundance of free PD-L1 on myeloid cells exhibited a significant positive correlation with Treg cell frequencies
  • A significantly reduced frequency of overall ILC3s in intestinal biopsies from Crohn's disease patients relative to healthy controls

Additionally, the study included bulk RNA sequencing on ILC3s sorted from inflamed and non-inflamed intestinal tissue from IBD patients, encompassing both Crohn's disease and ulcerative colitis. This analysis showed upregulation of CTLA4 in ILC3s from inflamed tissue.

This study not only provides new insights into the pathogenesis of IBD but also has implications for cancer immunotherapy, noted investigators. CTLA-4 blockade is used to enhance anti-tumor immune responses; however, it often leads to gut inflammation as a side effect. Targeting CTLA-4 on ILC3s may contribute to this adverse event; more selective therapies could potentially improve outcomes.

It's worth noting that while these findings are significant, the relatively small sample size for human data suggests that further validation in larger cohorts may be necessary to fully establish the clinical relevance of this pathway in IBD.

The authors declared no competing interests.