IL-10 induces CCR6 expression during Langerhans cell development while IL-4 and IFN-gamma suppress it

Immune responses are initiated, by dendritic cells (DC) that form a network comprising different populations. In particular, Langerhans cells (LC) app ear as a unique population of cells colonizing epithelial surfaces. We have recently shown that macrophage-inflammatory protein-3 alpha /CCL20, a chem okine secreted by epithelial cells, induces the selective migration of LC a mong DC populations. In this study, we investigated the effects of cytokine s on the expression of the CCL20 receptor, CCR6, during differentiation of LC. We found that both IL-4 and IFN-gamma blocked the expression of CCR6 an d CCL20 responsiveness at different stages of LC development. The effect of IL-4 was reversible and most likely due to the transient blockade of LC di fferentiation. In contrast, IFN-gamma -induced CCR6 loss was irreversible a nd was concomitant to the induction of DC maturation. When other cytokines involved in DC and T cell differentiation were tested, we found that IL-10, unlike IL-4 and IFN-gamma, maintained CCR6 expression. The effect of IL-10 was reversible and upon IL-10 withdrawn, CCR6 was lost concomitantly to fi nal LC differentiation. In addition, IL-10 induced the expression of CCR6 a nd responsiveness to CCL20 in differentiated monocytes that preserve their ability to differentiate into mature DC. Finally, TGF-beta, which induces L C differentiation, did not alter early CCR6 expression, but triggered its i rreversible down-regulation, in parallel to terminal LC differentiation. Ta ken together, these results suggest that the recruitment of LC at epithelia l surface might be suppressed during Th1 and Th2 immune responses, and ampl ified during regulatory immune responses involving IL-10 and TGF-beta.