CCL21 defect impairs dendritic cell trafficking in SAMP1/YitFc mice (MUC2P.817)

SAMP1/YitFc (SAMP) mice develop chronic ileitis similar to Crohn’s disease. The disease mechanism is unknown but thought to involve adaptive and innate immune responses. Here, we discovered that the chemokine CCL21, a ligand for CCR7, is almost completely absent in mesenteric lymphatics and other tissues of SAMP mice. Lymphatic CCL21 is known to be required for dendritic cell (DC) trafficking. Absence of CCL21 results in a severe defect of CD11b+CD103+ DC migration from the ileal lamina propria to the mesenteric lymph nodes (MLN), similar to the defect seen in CCR7-deficient mice. The ability of DCs to produce retinoic acid (RA) supporting regulatory T cells (Tregs) is also drastically reduced in SAMP mice. In young mice, the defects in CCL21 expression and DC trafficking preceded the clinical manifestation of ileitis. As a therapeutic intervention, we mobilized DCs by oral treatment with the TLR7 ligand R848, which increased Tregs in MLN and dramatically improved disease scores. Thus, absence of CCL21 expression represents a major pathogenic defect contributing to ileitis in SAMP mice. Our data suggest that therapies aimed at improved DC trafficking might be useful in patients with Crohn’s disease.