Pglyrp1-Cre marks distinct epithelial and immune lineages across mucosal sites.

Mucosa-associated lymphoid tissue (MALT) initiates immune responses at mucosal entry sites. Within MALT, microfold (M) cells sample luminal Ags and deliver them to underlying immune cells. Despite their functional importance, few tools enable selective manipulation of M cells in vivo. Here we report the generation and characterization of a peptidoglycan recognition protein 1 (Pglyrp1)-Cre knock-in mouse designed to provide conditional genetic access to M cells. Using Rosa26-tdTomato reporter mice, we found strong Pglyrp1 promoter activity in gut epithelial cells, including goblet and M cells, whereas activity in nasal-associated lymphoid tissue (NALT) was more heterogeneous and skewed toward immune cells, particularly neutrophils. To functionally interrogate Pglyrp1-expressing cells, we performed Cre-mediated ablation using 3 DTA-based models. The Rosa26GFP-DTA line caused marked perinatal lethality in double-positive pups, suggesting essential roles for Pglyrp1-positive cells early in life. In contrast, Rosa26DTA and Rosa26iDTR crosses produced minimal depletion of mucosal populations, including M cells, even at the highest nonlethal diphtheria toxin dose. These findings demonstrate differential Pglyrp1 promoter activity across mucosal tissues and highlight challenges in achieving M cell-specific targeting. Although not M cell-restricted, the Pglyrp1-Cre mouse provides a useful tool for manipulating Pglyrp1-expressing lineages and probing their roles in mucosal homeostasis and immunity.