Cyclosporin A and tacrolimus, but not rapamycin, inhibit MHC-restricted antigen presentation pathways in dendritic cells

Abstract

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 IntroductionDendritic cells (DCs) play a key role in the initiation of primary immune responses. 1 DCs can acquire and process antigens in the periphery, and migrate to secondary lymphoid tissues where they prime primary T-cell responses. Two distinct pathways have been known for the presentation of antigenic peptides on major histocompatibility complex (MHC) molecules. 2 Exogenous antigens internalized by phagocytosis or endocytosis are normally processed and loaded on class II MHC molecules in a post-Golgi compartment. In contrast, endogenous antigens are partially digested by proteosome, transferred into endoplasmic reticulum (ER) by a transporter associated with antigen presentation (TAP), and then loaded on class I MHC molecules. It is also known that DCs can uptake antigens from cells undergoing apoptosis or necrosis for presentation to class I MHC-restricted cytotoxic T lymphocytes (CTLs). This form of antigen presentation has been termed "cross-presentation." Crosspresentation has been demonstrated to occur for many viral antigens and also for tumor antigens. 3,4 Cross-presentation may be a mechanism by which naive T cells can be primed to antigens that are present in nonprofessional antigen-presenting cells (APCs). In the absence of such a mechanism, viral or tumor antigens expressed in nonprofessional APCs could escape immunosurveillance because CTL responses can only be induced efficiently for the antigens presented via class I MHC molecules on professional APCs. [5][6][7] Thus far, the main cellular targets for CsA and tacrolimus have been considered to be activated T cells, but not APCs. 8 Even though chemically unrelated, CsA and tacrolimus bind to and inhibit the same protein, calcineurin, in a calcium-dependent signaling pathway after formation of a complex with cyclophilin A and FK-506 binding proteins (FKBPs), respectively, resulting in inhibition of the transcription of interleukin 2 (IL-2) and other lymphokines. 9,10 Rapamycin has structural similarity with tacrolimus and even forms a complex with the same FKBPs that form a complex with tacrolimus. 11 However, the FKBP-rapamycin complex interacts with a protein distinct from calcineurin, termed the mammalian target of rapamycin, mTOR. 12 Rapamycin suppresses T-cell activation at a different level, mainly through inhibition of cell-cycle progression via suppression of p70 S6 kinase activation induced by growthpromoting lymphokines. 8 Because T-cell responses can only be initiated on recognition of peptide-MHC complexes presented by professional APCs, inhibitors of antigen processing p...

Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells

“…As shown here, the treatment of DCs with rapamycin augments a Th1 response ( Figure 7A). Because rapamycin does not alter antigen uptake and presentation, 35 or the expression level of costimulatory molecules such as CD80 and CD86 in DCs, 36 the enhancement of a Th1 response by rapamycin is probably the result of the augmentation of IL-12 production. In addition, the inhibition of GSK3 by LiCl suppressed a Th1-mediated immune response against L major in vivo ( Figure 7B).…”

Cyclical Expression of EBV Latent Membrane Protein 1 in EBV-Transformed B Cells Underpins Heterogeneity of Epitope Presentation and CD8+ T Cell Recognition

“…3 and 4). That slight reduction could be due either to some CSA-mediated impairment of Agpresenting function in the target cells themselves (34), or, more likely, to the fact that the IFN-␥ normally produced in CD8 ϩ T cell-LCL cocultures might further enhance Ag presentation by the LCL. Whatever the explanation for this slight effect, the overall results in conjunction with the Transwell assays clearly showed that cytokines are not the primary mechanism of T cell-mediated growth control, and instead refocused attention on a cytotoxic mechanism, perhaps through slow killing not detectable in 5-h assays.…”

Gag- and Nef-specific CD4+T cells recognize and inhibit SIV replication in infected macrophages early after infection

“…Then, at various time points after infection, we treated the MDM with the calcineurin inhibitor FK-506 to block the transport of newly epitope-loaded MHC-II molecules to the cell surface. FK-506 has been previously shown to block presentation of both exogenous and endogenous antigen while not interfering with T cell cytokine secretion (24,25). Therefore, addition of 4 nM FK-506 effectively paused MHC-II antigen presentation, allowing us to assess the kinetics of MHC-II antigen presentation in detail.…”