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* Laboratory of Immunodynamics, Department of Microbiology and Immunology and
World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan;
Key Laboratory of Bio-organic Chemistry, College of Bioengineering, Dalian University, Dalian, China,
Department of Glycotherapeutics, Osaka University Graduate School of Medicine, Osaka, Japan; and
¶ Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan
A number of chemokines, including CCL21, CCL19, CXCL12, and CXCL13, are coexpressed on the lumen or basal lamina of high endothelial venules (HEVs) in lymph nodes (LNs) and Peyer’s patches (PPs), consistent with the idea that they might cooperate to regulate lymphocyte trafficking into these lymphoid tissues. In this study we report that CXCL12, acting through its receptor, CXCR4, cooperates with CCR7 ligands to promote T cell trafficking across HEVs. CXCL12 enhanced the CCR7-induced chemotaxis of wild-type but not CXCR4-deficient T cells in vitro at suboptimal concentrations of a CCR7 ligand, but without affecting the expression level or ligand-binding ability of CCR7. Real-time chemotaxis analysis showed that CXCL12 substantially shortened the lag time before cell migration began in vitro, but not the migration speed of T cells responding to suboptimal CCR7 ligand concentrations. In addition, CXCL12 augmented the CCR7 ligand-driven ERK phosphorylation and actin polymerization in T cells under the same conditions. In adoptive transfer experiments, CXCL12 promoted naive T cell trafficking to LNs and PPs in wild-type but not CCR7 ligand-deficient plt/plt recipient mice; this increased T cell trafficking was associated with enhanced binding of the T cells to HEVs and their subsequent migration into the LN parenchyma. Thus, CXCL12 synergizes with CCR7 ligands to promote T cell migration by sensitizing T cells through CXCR4, thus enabling them to respond to lower concentrations of CCR7 ligands. Such concerted action of chemokines provides an additional, previously unknown mechanism for efficient lymphocyte trafficking across HEVs into LNs and PPs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Z.B. and H.H. contributed equally to this work.
2 Address correspondence and reprint requests to Dr. Masayuki Miyasaka, Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine (C8), 2-2, Yamada-oka, Suita 565-0871, Japan. E-mail address: mmiyasak{at}orgctl.med.osaka-u.ac.jp
3 Abbreviations used in this paper: HEV, high endothelial venule; LN, lymph node; MLN, mesenteric lymph node; PP, Peyer’s patch.
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