Bai Zhongbin, Hayasaka Haruko, Kobayashi Masayoshi, Li Wenzhe, Guo Zijin, Jang Myoung Ho, Kondo Akihiro, Choi Byung-il, Iwakura Yoichiro, Miyasaka Masayuki
Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University, Osaka, Japan.
J Immunol. 2009 Feb 1;182(3):1287-95. doi: 10.4049/jimmunol.182.3.1287.
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.
包括CCL21、CCL19、CXCL12和CXCL13在内的多种趋化因子在淋巴结（LN）和派尔集合淋巴结（PP）的高内皮微静脉（HEV）的管腔或基膜上共同表达，这与它们可能协同调节淋巴细胞向这些淋巴组织的归巢的观点一致。在本研究中，我们报道CXCL12通过其受体CXCR4发挥作用，与CCR7配体协同促进T细胞穿越HEV的归巢。在CCR7配体的亚最佳浓度下，CXCL12在体外增强了野生型而非CXCR4缺陷型T细胞的CCR7诱导的趋化作用，但不影响CCR7的表达水平或配体结合能力。实时趋化分析表明，CXCL12在体外显著缩短了细胞迁移开始前的延迟时间，但不影响T细胞对亚最佳CCR7配体浓度的迁移速度。此外，在相同条件下，CXCL12增强了CCR7配体驱动的T细胞中的ERK磷酸化和肌动蛋白聚合。在过继转移实验中，CXCL12促进野生型而非CCR7配体缺陷型plt/plt受体小鼠中幼稚T细胞向LN和PP的归巢；这种增加的T细胞归巢与T细胞与HEV的结合增强及其随后向LN实质的迁移有关。因此，CXCL12与CCR7配体协同作用，通过CXCR4使T细胞敏感化来促进T细胞迁移，从而使它们能够对更低浓度的CCR7配体作出反应。趋化因子的这种协同作用为淋巴细胞有效穿越HEV进入LN和PP提供了一种额外的、以前未知的机制。
