IMMUNOBIOLOGY

The initiation of immune responses is associated with the maturation of den-dritic cells (DCs) and their migration to draining lymph nodes. En route activated DCs encounter cells of the tissue micro-environment, such as fibroblasts. Be-cause we have shown that DCs interact with fibroblasts during immune re-sponses, we studied the impact of skin fibroblasts on human monocyte-derived DC function and subsequent human T-cell (TC) differentiation. We show that fibroblasts support interleukin-23 (IL-23) secretion from DCs preactivated by lipo-polysaccharide (DCact) compared with lipopolysaccharide-activated DCs alone. The underlying complex feedback-loop mechanism involves IL-1/tumor necro-sis factor- (from DCact), which stimulate fibroblasts prostaglandin E2 production. Prostaglandin E2, in turn, acts on DCact and increases their IL-23 release. Further-more, fibroblast-stimulated DCact are far superior to DCact alone, in promoting the expansion of Th17 cells in a Cox-2-, IL-23-dependent manner. Using CD4CD45RO memory TCs and CD4CD45RA naive TCs, we showed that fibroblasts induce a phenotype of DCact that promotes the expansion of Th17 cells. Moreover, in psoriasis, a prototypic immune response in which the importance of IL-23/Th17 is known, high expression of Cox-2 in fibro-blasts was observed. In conclusion, skin fibroblasts are involved in regulation of IL-23 production in DCs and, as a result, of Th17 expansion. (Blood. 2010;116(10): 1715-1725