Myoung Ho Jang2,*, Nagako Sougawa2,*, Toshiyuki Tanaka*, Takako Hirata†, Takachika Hiroi‡, Kazuo Tohya§, Zijin Guo*, Eiji Umemoto*, Yukihiko Ebisuno*, Bo-Gie Yang*, Ju-Young Seoh¶, Martin Lipp||, Hiroshi Kiyono‡ and Masayuki Miyasaka3,*
* Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, and †21st Century Center of Excellence Program, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; ‡Division of Mucosal Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; §Department of Anatomy, Kansai College of Oriental Medicine, Osaka, Japan; ¶ Department of Microbiology, College of Medicine, Ewha Woman’s University, Seoul, Korea; and || Max Delbruck Center for Molecular Medicine, Berlin, Germany
Although dendritic cells (DCs) located in the small intestinal lamina propria (LP-DCs) migrate to mesenteric lymph nodes (MLNs) constitutively, it is unclear which chemokines regulate their trafficking to MLNs. In this study we report that LP-DCs in unperturbed mice require CCR7 to migrate to MLNs. In vitro, LP-DCs expressing CCR7 migrated toward CCL21, although the LP-DCs appeared morphologically and phenotypically immature. In MLNs, DCs bearing the unique LP-DC phenotype (CD11chighCD8αintCD11blowαLlowβ7high and CD11chighCD8α-CD11bhighαLlowβ7high) were abundant in wild-type mice, but were markedly fewer in CCL19-, CCL21-Ser-deficient plt/plt mice and were almost absent in CCR7-deficient mice, indicating the critical importance of CCR7 in LP-DC trafficking to MLNs. Interestingly, CCR7+ DCs in MLNs with the unique LP-DC phenotype had numerous vacuoles containing cellular debris in the cytoplasm, although MLN-DCs themselves were poorly phagocytic, suggesting that the debris was derived from the LP, where the LP-DCs ingested apoptotic intestinal epithelial cells (IECs). Consistent with this, LP-DCs ingested IECs vigorously in vitro. By presenting IEC-associated Ag, the LP-DCs also induce T cells to produce IL-4 and IL-10. Collectively, these results strongly suggest that LP-DCs with unique immunomodulatory activities migrate to MLNs in a CCR7-dependent manner to engage in the presentation of IEC-associated Ags acquired in the LP.