Divergent ILC3 responses to PDGF-D control mucosal immunity

group 3 innate lymphoid cells (ILC3s). However, mice lack NKp44, raising the question of whether PDGF-D regulates murine ILC3s through a distinct pathway. We show that PDGF-D promoted interleukin-22 (IL-22) production and ILC3 proliferation in mice through PDGF receptor β (PDGFRβ), a canonical receptor absent in human ILC3s. Mice lacking PDGFRβ in ILC3s were susceptible to enteric infections. Using NKp44-transgenic mice, we demonstrate that PDGF-D engagement of NKp44 instead induced a type 1 effector program marked by tumor necrosis factor-α and interferon-γ (IFN-γ) production. Although early IFN-γ release protected mice from enteric infections, sustained IFN-γ was detrimental. Tissue localization analysis with a PDGF-D reporter identified fibroblasts and endothelial cells as inflammation-responsive PDGF-D sources. These findings reveal evolutionarily divergent PDGF-D sensing mechanisms in ILC3s and uncover their differential contributions to mucosal immunity during infection.