CCL25 induces α4β7 integrin-dependent migration of IL-17+γδ T lymphocytes during an allergic reaction

Herein, we provide evidence that during allergic inflammation, CCL25 induces the selec-tive migration of IL-17+ ?d T cells mediated by a4 beta 7 integrin. Intrapleural injection of CCL25 into ovalbumin (OVA)-immunized C57BL/6 mice triggered the accumulation of ?d T lymphocytes expressing CCR9 (CCL25 receptor) and a4 beta 7 integrin in the pleura, but failed to attract a beta T lymphocytes. CCL25 attracted CCR6+ ?d T cells producing IL-17 (but not IFN-? or IL-4). OVA challenge triggered increased production of CCL25 followed by the accumulation of CCR9+, a4 beta 7+, and CCR6+/IL-17+ ?d T cells into the pleural cavities of OVA-immunized mice, which was inhibited by the in vivo neutralization of CCL25. The in vivo blockade of a4 beta 7 integrin also inhibited the migration of IL-17+ ?d T lymphocytes (but not of a beta T lymphocytes) into mouse pleura after OVA challenge, suggesting that the CCL25/a4 beta 7 integrin pathway is selective for ?d T cells. In addition, a4 beta 7 integrin blockade impaired the in vitro transmigration of ?d T cells across endothelium (which expresses a4 beta 7 ligands VCAM-1 and MadCAM-1), which was induced by CCL25 and by cell-free pleural washes recovered from OVA-challenged mice. Our results reveal that during an allergic reaction, CCL25 drives IL-17+ ?d T-cell mobilization to inflamed tissue via a4 beta 7 integrin and modulates IL-17 levels.