Leukotriene B4 mediates γδ T lymphocyte migration in response to diverse stimuli

Herein, we investigated the involvement of the 5-LO-derived lipid mediator LTB4 in gamma delta T cell migration. When injected into the i.pl. space of C57BL/6 mice, LTB4 triggered gamma delta T lymphocyte mobilization in vivo, a phenomenon also observed in in vitro chemotaxis assays. The i.pl. injection of Escherichia coli endotoxin (LPS) triggered increased levels of LTB4 in pleural cavities. The in vivo inhibition of LTB4 biosynthesis by the 5-LO inhibitor zileuton or the FLAP inhibitor MK886 attenuated LPS-induced gamma delta T cell accumulation into pleural cavities. Accordingly, 5-LO KO mice failed to recruit gamma delta T cells into the inflammatory site after i.pl. LPS. Antagonists of the high-affinity LTB4 receptor BLT1, CP105, 696, and LY292476 also attenuated LPS-induced gamma delta T cell accumulation in pleural cavities as well as in vitro chemotaxis toward pleural washes obtained from LPS-simulated mice. LTB4/BLT1 also accounted for gamma delta T cell migration induced by i.pl. administration of Mycobacterium bovis BCG or antigen in sensitized mice. BLT1 was expressed on naive, resident as well as LPS-recruited gamma delta T cells. Isolated gamma delta T cells were found to undergo F-actin cytoskeleton reorganization when incubated with LTB4 in vitro, confirming that gamma delta T lymphocytes can respond directly to LTB4. In addition to its direct effect on gamma delta T cells, LTB4 triggered their accumulation indirectly, via modulation of CCL2 production in mouse pleural cavities. These data show that gamma delta T cell migration into the pleural cavity of mice during diverse inflammatory responses is dependent on LTB4/BLT1. J. Leukoc. Biol. 87: 323-332; 2010.