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

Abstract

Herein, we provide evidence that during allergic inflammation, CCL25 induces the selective migration of IL-17(+) γδ T cells mediated by α(4) β(7) integrin. Intrapleural injection of CCL25 into ovalbumin (OVA)-immunized C57BL/6 mice triggered the accumulation of γδ T lymphocytes expressing CCR9 (CCL25 receptor) and α(4) β(7) integrin in the pleura, but failed to attract αβ T lymphocytes. CCL25 attracted CCR6(+) γδ T cells producing IL-17 (but not IFN-γ or IL-4). OVA challenge triggered increased production of CCL25 followed by the accumulation of CCR9(+) , α(4) β(7) (+) , and CCR6(+) /IL-17(+) γδ 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 α(4) β(7) integrin also inhibited the migration of IL-17(+) γδ T lymphocytes (but not of αβ T lymphocytes) into mouse pleura after OVA challenge, suggesting that the CCL25/α(4) β(7) integrin pathway is selective for γδ T cells. In addition, α(4) β(7) integrin blockade impaired the in vitro transmigration of γδ T cells across endothelium (which expresses α(4) β(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(+) γδ T-cell mobilization to inflamed tissue via α(4) β(7) integrin and modulates IL-17 levels.