Interleukin-17D regulates group 3 innate lymphoid cell function through its receptor CD93.

Area of Science:

• Immunology
• Gastroenterology
• Microbiology

Background:

• The interleukin-17 (IL-17) family plays a dual role in host defense and autoimmune diseases.
• IL-17D is a less-understood member of the IL-17 family with potential roles in immunity.

Purpose of the Study:

• To investigate the function of IL-17D in the context of intestinal homeostasis and disease.
• To identify the receptor and mechanism through which IL-17D exerts its effects.

Main Methods:

• Utilized Il17d knockout (Il17d-/-) mice to assess susceptibility to colitis, bacterial infection, and colon cancer.
• Examined IL-22 production by group 3 innate lymphoid cells (ILC3s) and expression of antimicrobial peptides (RegIIIβ, RegIIIγ).
• Performed protein purification and binding assays to identify the IL-17D receptor, and used Cd93 conditional knockout mice.

Main Results:

• Il17d deficiency led to increased susceptibility to acute colitis, bacterial infection, and experimental colon cancer.
• IL-17D deficiency impaired IL-22 production by ILC3s and reduced expression of key antimicrobial peptides.
• IL-17D binds to CD93 on ILC3s, and loss of CD93 in ILC3s phenocopies IL-17D deficiency, impairing IL-22 production and worsening colitis.

Conclusions:

• The IL-17D-CD93 axis is critical for regulating ILC3 function and maintaining intestinal homeostasis.
• IL-17D plays a protective role in the gut by promoting IL-22-dependent antimicrobial responses.
• Targeting the IL-17D-CD93 pathway may offer therapeutic potential for inflammatory bowel diseases and related conditions.