SELECTIVE RECRUITMENT OF IMMATURE AND MATURE DENDRITIC CELLS BY DISTINCT CHEMOKINES EXPRESSED IN DIFFERENT ANATOMIC SITES

DCs (dendritic cells) function as sentinels of the immune system. They traffic from the blood to the tissues where, while immature, they cap ture antigens. They then leave the tissues and move to the draining ly mphoid organs where, converted into mature DC, they prime naive T cell s. This suggestive link between DC traffic pattern and functions led u s to investigate the chemokine responsiveness of DCs during their deve lopment and maturation. DCs were differentiated either from CD34(+) he matopoietic progenitor cells (HPCs) cultured with granulocyte/macropha ge colony-stimulating factor (GM-CSF) plus tumor necrosis factor (TNF) -alpha or from monocytes cultured with GM-CSF plus interleukin 4. Imma ture DCs derived from CD34(+) HPCs migrate most vigorously in response to macrophage inflammatory protein (MIP)-3 alpha, but also to MIP-1 a lpha and RANTES (regulated on activation, normal T cell expressed and secreted). Upon maturation, induced by either TNF-alpha, lipopolysacch aride, or CD40L, DCs lose their response to these three chemokines whe n they acquire a sustained responsiveness to a single other chemokine, MIP-3 beta. CC chemokine receptor (CCR)6 and CCR7 are the only known receptors for MIP-3 alpha and MIP-SP, respectively. The observation th at CCR6 mRNA expression decreases progressively as DCs mature, whereas CCR7 mRNA expression is sharply upregulated, provides a likely explan ation for the changes in chemokine responsiveness. Similarly, MIP-3 be ta responsiveness and CCR7 expression are induced upon maturation of m onocyte-derived DCs. Furthermore, the chemotactic response to MIP-3 be ta is also acquired by CD11c(+) DCs isolated fi-om blood after spontan eous maturation. Finally, detection by in situ hybridization of MIP-3 alpha mRNA only within inflamed epithelial crypts of tonsils, and of M IP-3 beta mRNA specifically in T cell-rich areas, suggests a role for MIP-3 alpha/CCR6 in recruitment of immature DCs at site of injury and for MIP-3 beta/CCR7 in accumulation of antigen-loaded mature DCs in T cell-rich areas.