P-200 CCL21 Defect Impairs Dendritic Cell Trafficking in SAMP1/YitFc Mice

Abstract

The lymphatic chemokine CCL21 is required for dendritic cell (DC) trafficking from tissues to lymph nodes. Migratory DCs are crucial in establishing tolerance towards foreign yet harmless antigens. Here, we discovered that CCL21 is almost completely absent in ileitis-prone SAMP1/YitFc (SAMP) mice, and DC migration is severely impaired. We investigated whether mobilizing DCs by oral treatment with R848 can attenuate ileitis. We used SAMP mice which develop spontaneous chronic ileitis similar to Crohn's disease. We measured CCL21 expression by quantitative polymerase chain reaction and immunofluorescence, and spontaneous or induced DC migration by flow cytometry. We analyzed DC production of retinoic acid and their ability to induce regulatory T cells (Tregs). The impact of DC trafficking on ileitis was assessed by feeding mice with the Toll-like receptor 7 ligand R848. SAMP mice express almost no CCL21 and have severe defect of CD11b+CD103+ DC migration from the ileal lamina propria to the mesenteric lymph nodes (MLN), similar to the defect seen in mice lacking CCR7, the receptor for CCL21. The ability of DCs to produce retinoic acid supporting Tregs was also drastically reduced in SAMP mice. In young mice, the defects in CCL21 expression and DC trafficking preceded the clinical manifestation of ileitis. Treatment with R848 enhanced DC migration, increased Tregs in MLN and dramatically improved disease scores. We identify the absence of CCL21 as the 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.