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 antigens and deliver them to underlying immune cells. Despite their functional importance, few tools enable selective manipulation of M cells <i>in vivo</i>. Here we report the generation and characterization of a peptidoglycan recognition protein 1 (<i>Pglyrp1</i>-Cre knock-in mouse designed to allow conditional genetic access to M cells. Using Rosa26-tdTomato reporter mice, we found strong <i>Pglyrp1</i> promoter activity in gut epithelial cells, including goblet and M cells, whereas activity in nasal-associated lymphoid tissue (NALT) was more heterogeneous and skewed towards immune cells, particularly neutrophils. To functionally interrogate <i>Pglyrp1</i>-expressing cells, we performed Cre-mediated ablation using three DTA-based models. The Rosa26^GFP-DTA line caused marked perinatal lethality in double-positive pups, suggesting essential roles for Pglyrp1-positive cells early in life. In contrast, Rosa26^DTA and Rosa26^iDTR crosses produced minimal depletion of mucosal populations, including M cells, even at the highest non-lethal diphtheria toxin dose. These findings demonstrate tissue-specific <i>Pglyrp1</i> promoter activity 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.