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CTLA-4-expressing ILC3s restrain interleukin-23-mediated inflammation
Anees Ahmed1,2,3, Ann M Joseph1,2,3, Jordan Zhou1,2,3
1Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology & Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
Nature
|June 12, 2024
Summary
Interleukin-23 (IL-23) can cause inflammation but also protect the gut. We found that cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) on ILC3 cells acts as a crucial brake, preventing IL-23
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- Interleukin-23 (IL-23) plays a dual role in the intestine, mediating chronic inflammation and promoting tissue protection.
- The precise mechanisms governing IL-23's beneficial versus pathological effects are not fully understood.
Purpose of the Study:
- To investigate the cellular response to IL-23 in the intestine and identify mechanisms regulating its functions.
- To explore the role of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) on intestinal immune cells.
Main Methods:
- Single-cell RNA sequencing of IL-23 receptor-expressing cells in the mouse intestine.
- Analysis of gene expression and cellular responses following IL-23 stimulation.
- Genetic manipulation of CTLA-4 expression in ILC3s and assessment of inflammatory outcomes in mice.
- Correlation analysis of CTLA-4 expression in human ILC3s with inflammatory bowel disease.
Main Results:
- IL-23 receptor expression is dominated by T cells and group 3 innate lymphoid cells (ILC3s).
- ILC3s unexpectedly upregulate the immunoregulatory molecule CTLA-4 in response to IL-23 and gut microbes, dependent on FOXO1 and STAT3.
- Loss of CTLA-4 on ILC3s leads to reduced regulatory T cells, increased inflammatory T cells, and exacerbated intestinal inflammation.
- ILC3-derived CTLA-4 suppresses co-stimulatory molecules and enhances PD-L1 on myeloid cells, dampening inflammation.
- Human ILC3s upregulate CTLA-4 during gut inflammation, correlating with disease severity in inflammatory bowel disease.
Conclusions:
- ILC3-intrinsic CTLA-4 functions as a critical checkpoint, mitigating the pathological effects of IL-23 in the intestine.
- Disruption of CTLA-4 on ILC3s, observed in inflammatory bowel disease, contributes to chronic intestinal inflammation.
- Targeting the IL-23-CTLA-4 axis on ILC3s may offer therapeutic strategies for chronic inflammatory diseases.
