Rapamycin impairs antigen uptake of human dendritic cells.
BACKGROUND
Rapamycin is a recently introduced immunosuppressive agent. Its effect on lymphocytes has been extensively studied. Whether it can also modulate dendritic cell (DC) function is unknown.


METHODS
The effect of rapamycin on differentiation, antigen uptake, and the immunostimulatory capacity of human DC was examined. DC were derived from monocytes upon culture with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence or absence of rapamycin (0.1-100 ng/mL). Surface phenotype and antigen uptake capacity of DC were assessed by flow cytometry. Immunostimulatory capacity was measured by mixed lymphocyte culture.


RESULTS
Rapamycin reduced DC recovery and increased DC apoptosis. DC differentiated in the presence of rapamycin (rapa-DC) had increased expression of CD1a, CD1b, and CD1c and decreased expression of MHC I, MHC II, CD80, CD86, and CD40. Antigen uptake receptor expression (mannose receptor, CD32, CD91, CD46) was decreased, and receptor-mediated endocytosis of fluorescein isothiocyanate-dextran was markedly impaired in rapa-DC, as were fluid phase endocytosis of Lucipher Yellow and phagocytic activity of bacteria and dead or apoptotic cells. CD40 ligand-induced production of both IL-12 and IL-10 was reduced in rapa-DC, and allogeneic T lymphocyte responses were moderately impaired when rapa-DC were used as stimulator cells. Neither cyclosporine nor FK506 affected DC function. However, the effects of rapamycin on DC could be completely inhibited by a 10-fold excess of FK506 but not by up to 100-fold excess of cyclosporine.


CONCLUSIONS
Rapamycin has a unique and profound inhibitory effect on DC function, which seems to be at least in part mediated by the FKBP immunophilins.
Monti
Paolo
P
Laboratory of Experimental Surgery, Surgical Department, S. Raffaele Scientific Institute, Milan, Italy.
Mercalli
Alessia
A
Leone
Biagio Eugenio
BE
Valerio
Di Carlo
DC
Allavena
Paola
P
Piemonti
Lorenzo
L
D000941:Antigens / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D016764:Cell Polarity; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004705:Endocytosis / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D022061:Tacrolimus Binding Protein 1A / Q000502:physiology
D000941:Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus