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Pivotal Role of Dendritic Cell–derived CXCL10 in the Retention of T Helper Cell 1 Lymphocytes in Secondary Lymph Nodes

Hiroyuki Yoneyama^1,2, Shosaku Narumi¹, Yanyun Zhang¹, Masako Murai^1,2, Marco Baggiolini³, Antonio Lanzavecchia⁴, Takafumi Ichida², Hitoshi Asakura² and Kouji Matsushima¹

¹ Department of Molecular Preventive Medicine, School of Medicine and Core Research and Evolutional Science and Technology (CREST), The University of Tokyo, Tokyo 113-0033, Japan
² Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8122, Japan
³ Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland
⁴ Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland

Address correspondence to Kouji Matsushima, Dept. of Molecular Preventive Medicine, School of Medicine and Core Research and Evolutional Science and Technology (CREST), The University of Tokyo, Bunkyoku, Tokyo 113-0033, Japan. Phone: 81-3-5841-3431; Fax: 81-3-5684-2297; E-mail: koujim{at}m.u-tokyo.ac.jp

Various immune diseases are considered to be regulated by the balance of T helper (Th)1 and Th2 subsets. Although Th lymphocytes are believed to be generated in draining lymph nodes (LNs), in vivo Th cell behaviors during Th1/Th2 polarization are largely unexplored. Using a murine granulomatous liver disease model induced by Propionibacterium acnes, we show that retention of Th1 cells in the LNs is controlled by a chemokine, CXCL10/interferon (IFN) inducible protein 10 produced by mature dendritic cells (DCs). Hepatic LN DCs preferentially produced CXCL10 to attract 5'-bromo-2'-deoxyuridine (BrdU)⁺CD4⁺ T cells and form clusters with IFN-–producing CD4⁺ T cells by day 7 after antigen challenge. Blockade of CXCL10 dramatically altered the distribution of cluster-forming BrdU⁺CD4⁺ T cells. BrdU⁺CD4⁺ T cells in the hepatic LNs were selectively diminished while those in the circulation were significantly increased by treatment with anti-CXCL10 monoclonal antibody. This was accompanied by accelerated infiltration of memory T cells into the periphery of hepatic granuloma sites, most of them were in cell cycle and further produced higher amount of IFN- leading to exacerbation of liver injury. Thus, mature DC-derived CXCL10 is pivotal to retain Th1 lymphocytes within T cell areas of draining LNs and optimize the Th1-mediated immune responses.

Key Words: chemokine • dendritic cell • helper T cell • lymph node • liver

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