Leukotriene C4 induces migration of human monocyte-derived dendritic cells without loss of immunostimulatory function

Generation of human monocyte-derived dendritic cells (DCs) for cancer vaccination involves ex vivo maturation in the presence of proinflammatory cytokines and prostaglandin E(2) (PGE₂). Although the inclusion of PGE₂ during maturation is imperative for the induction of DC migration, PGE₂ has unfavorable effects on the immunostimulatory capacity of these cells. Like PGE₂, leukotrienes (LTs) are potent mediators of DC migration. We therefore sought to characterize the migratory and immunologic properties of DCs that matured in the presence of LTB₄, LTC₄, LTD₄, and PGE₂. Here, we demonstrate that DCs matured in the presence of LTC₄, but not LTB₄ or LTD₄, are superior to PGE₂-matured DCs in stimulating CD4⁺ T-cell responses and in inducing antigen-specific cytotoxic T lymphocytes (CTLs) in vitro without concomitant induction or recruitment of regulatory T cells (Tregs). LTC₄-matured DCs migrate efficiently through layers of extracellular matrix and secrete higher levels of immunostimulatory IL-12p70 while producing reduced levels of immuneinhibitory IL-10, IL12p40, indoleamine-2,3-dioxidase, and TIMP-1 (tissue inhibitor of matrix metalloproteinases). Intracellular calcium mobilization and receptor antagonist studies reveal that, in contrast to LTD₄, LTC₄ did not signal through CysLTR₁ in DCs. Collectively, our data suggest that LTC₄ represents a promising candidate to replace PGE ₂ in DC maturation protocols for cancer vaccination.