Cyclosporin A and tacrolimus, but not rapamycin, inhibit MHC-restricted antigen presentation pathways in dendritic cells.
The main targets for the immunosuppressive calcineurin inhibitors, cyclosporin A (CsA) and tacrolimus, have been considered to be activated T cells, but not antigen-presenting cells. Here we demonstrate that CsA and tacrolimus, but not rapamycin, inhibit major histocompatibility complex (MHC)-restricted antigen presentation in dendritic cells (DCs). Microencapsulated ovalbumin (OVA) was efficiently captured, processed, and presented on both class I MHC molecules (cross-presentation) as well as on class II MHC molecules. Addition of CsA and tacrolimus, but not rapamycin, to cultures of DCs inhibited both the class I processing pathway and the class II processing pathway of exogenous OVA. In addition, CsA and tacrolimus, but not rapamycin, also inhibited the classic class I processing pathway of endogenous OVA. CsA and tacrolimus did not inhibit presentation of exogenously added OVA peptide, SIINFEKL, phagocytic activity of DCs, or the total level of expression of class I MHC (H-2Kb) molecules. CsA and tacrolimus, however, inhibited profoundly the expression of SIINFEKL-H-2Kb complexes in OVA-phagocytized DCs. These results demonstrate clearly that CsA and tacrolimus inhibit intracellular processing events of antigens, and further suggest that the immunosuppressive activity of CsA and tacrolimus is at least in part due to inhibition of antigen processing pathways.
Lee
Young-Ran
YR
College of Pharmacy, Chungbuk National University, Cheongju 361-763, South Korea.
Yang
In-Ho
IH
Lee
Young-Hee
YH
Im
Sun-A
SA
Song
Sukgil
S
Li
Hong
H
Han
Kun
K
Kim
Kyungjae
K
Eo
Seong Kug
SK
Lee
Chong-Kil
CK
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology; D000941:Antigens / Q000276:immunology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D013379:Substrate Specificity; D016559:Tacrolimus / Q000494:pharmacology*
D000941:Antigens; D006649:Histocompatibility Antigens; D010446:Peptide Fragments; D016572:Cyclosporine; D010047:Ovalbumin; D020123:Sirolimus; D016559:Tacrolimus