Divergent ILC3 responses to PDGF-D control mucosal immunity

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Platelet-derived growth factor D (PDGF-D) is a noncanonical ligand for human NKp44+ group 3 innate lymphoid cells (ILC3s).
• Murine ILC3s lack NKp44, necessitating investigation into alternative PDGF-D regulatory pathways in mice.

Purpose of the Study:

• To elucidate the distinct mechanisms by which PDGF-D regulates murine ILC3s.
• To understand the role of PDGF-D signaling in mucosal immunity and host defense against enteric infections.

Main Methods:

• Utilized PDGFRβ knockout mice and NKp44-transgenic mice to study PDGF-D-mediated ILC3 responses.
• Assessed interleukin-22 (IL-22), tumor necrosis factor-α, and interferon-γ (IFN-γ) production.
• Employed PDGF-D reporter mice for tissue localization analysis.

Main Results:

• PDGF-D promotes IL-22 production and ILC3 proliferation in mice via PDGF receptor β (PDGFRβ).
• PDGFRβ deficiency in ILC3s confers susceptibility to enteric infections.
• PDGF-D engagement of NKp44 in transgenic mice induces a type 1 effector program with both protective and detrimental IFN-γ production.
• Fibroblasts and endothelial cells identified as key PDGF-D sources during inflammation.

Conclusions:

• PDGF-D utilizes evolutionarily divergent sensing mechanisms in ILC3s, mediated by PDGFRβ in mice and NKp44 in humans.
• These divergent pathways differentially contribute to mucosal immunity and host defense during infection.